U.S. patent application number 12/378308 was filed with the patent office on 2009-08-20 for thienopyrroles and pyrrolothiazoles as new therapeutic agents.
Invention is credited to Dominique F. Bonafoux, Xiaoyun Wu.
Application Number | 20090209609 12/378308 |
Document ID | / |
Family ID | 40955706 |
Filed Date | 2009-08-20 |
United States Patent
Application |
20090209609 |
Kind Code |
A1 |
Bonafoux; Dominique F. ; et
al. |
August 20, 2009 |
Thienopyrroles and pyrrolothiazoles as new therapeutic agents
Abstract
The present invention is directed to novel compounds of Formula
(I) ##STR00001## wherein the variables are defined as herein. The
compounds of Formula (I) are useful as CRTH2 antagonists and as
such would be useful in treating certain conditions and diseases,
especially asthma, allergic asthma, allergic inflammation,
rhinitis, allergic rhinitis or atopic dermatitis.
Inventors: |
Bonafoux; Dominique F.;
(Cambridge, MA) ; Wu; Xiaoyun; (Westborough,
MA) |
Correspondence
Address: |
ABBOTT BIORESEARCH
100 RESEARCH DRIVE
WORCESTER
MA
01605-4314
US
|
Family ID: |
40955706 |
Appl. No.: |
12/378308 |
Filed: |
February 13, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61066046 |
Feb 15, 2008 |
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Current U.S.
Class: |
514/412 ;
548/453 |
Current CPC
Class: |
C07D 495/04 20130101;
A61P 11/06 20180101 |
Class at
Publication: |
514/412 ;
548/453 |
International
Class: |
A61K 31/407 20060101
A61K031/407; C07D 495/04 20060101 C07D495/04 |
Claims
1. A compound of Formula I ##STR00032## pharmaceutically acceptable
salts, biologically active metabolites, solvates, hydrates,
pro-drugs, enantiomers or stereoisomers thereof, wherein X is CH, S
or N; Y is CH, S or N; L is CO, SO, S(O).sub.2 or
(C.sub.1-C.sub.4)alkyl; A is optionally substituted aryl,
optionally substituted (C.sub.3-C.sub.6)cycloalkyl, optionally
substituted heteroaryl, optionally substituted heterocyclyl or
optionally substituted -aryl-S(O).sub.2-Z; wherein Z is
N(R.sup.5).sub.2, optionally substituted (C.sub.1-C.sub.6)alkyl,
optionally substituted (C.sub.3-C.sub.6)cycloalkyl or optionally
substituted heterocyclyl; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
independently H or (C.sub.1-C.sub.4)alkyl; and R.sup.5 is
independently H, (C.sub.1-C.sub.3)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, --CO--(C.sub.1-C.sub.6)alkyl, or
--CON(R.sup.1).sub.2; provided that X and Y are not both S, not
both CH.sub.2 and not both N.
2. The compound of claim 1 wherein X is CH.
3. The compound of claim 2 wherein Y is S.
4. The compound of claim 3 wherein L is S(O).sub.2.
5. The compound of claim 4 wherein A is optionally substituted
phenyl, optionally substituted naphthyl, optionally substituted
(C.sub.3-C.sub.6)cycloalkyl or optionally substituted
dihydrobenzofuranyl; and R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
independently H.
6. The compound of claim 5 wherein A is optionally substituted
phenyl, optionally substituted dihydrobenzofuranyl or optionally
substituted cyclopropyl; wherein the phenyl, the
dihydrobenzofuranyl or the cyclopropyl is optionally substituted
with one or more substituents independently selected from halogen,
CN, OH, --SO.sub.2--(C.sub.1-C.sub.6)alkyl,
--SO.sub.2--(C.sub.3-C.sub.6)cycloalkyl,
--O--(C.sub.1-C.sub.4)alkyl and optionally substituted
(C.sub.1-C.sub.6)alkyl.
7. The compound of claim 1 wherein X is S.
8. The compound of claim 7 wherein Y is CH.
9. The compound of claim 8 wherein L is S(O).sub.2 or
(C.sub.1-C.sub.4)alkyl.
10. The compound of claim 9 wherein A is optionally substituted
aryl, optionally substituted heteroaryl or optionally substituted
-aryl-S(O).sub.2-Z; wherein Z is N(R.sup.5).sub.2, optionally
substituted (C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.3-C.sub.6)cycloalkyl or optionally substituted heterocyclyl;
and R.sup.5 is independently H, (C.sub.1-C.sub.3)alkyl, or
(C.sub.3-C.sub.6)cycloalkyl, --CO--(C.sub.1-C.sub.6)alkyl, or
--CON(R.sup.1).sub.2.
11. The compound of claim 10 wherein R.sup.2 and R.sup.3 are H.
12. The compound of claim 11 wherein A is optionally substituted
isoxazolyl, optionally substituted naphthyl, optionally substituted
phenyl, optionally substituted pyridinyl or -optionally substituted
phenyl-S(O).sub.2-Z; wherein Z is CH.sub.3, --N(CH.sub.3).sub.2,
--N(CH.sub.3)cyclohexyl, optionally substituted morpholinyl or
optionally substituted pyrrolidinyl.
13. The compound of claim 12 wherein A is optionally substituted by
one or more substituents independently selected from halogen, CN,
CH.sub.3, --NH--C(O)--CH.sub.3, NHCON(CH.sub.3).sub.2, CF.sub.3,
--S(O).sub.2CH.sub.3, optionally substituted
(C.sub.1-C.sub.4)alkyl, --O--(C.sub.1-C.sub.4)alkyl and
pyrazolyl.
14. The compound of claim 13 wherein R.sup.1 is CH.sub.3 and
R.sup.4 is CH.sub.3.
15. The compound of claim 13 wherein R.sup.1 is H and R.sup.4 is H
or CH.sub.3.
16. The compound of claim 15 wherein L is CH.sub.2.
17. The compound of claim 16 wherein A is optionally substituted
isoxazolyl, optionally substituted phenyl or optionally substituted
-phenyl-S(O).sub.2-Z; wherein Z is CH.sub.3, --N(CH.sub.3).sub.2,
--N(CH.sub.3)cyclohexyl or optionally substituted morpholinyl.
18. The compound of claim 15 wherein L is S(O).sub.2.
19. The compound of claim 18 wherein A is optionally substituted
naphthyl, optionally substituted phenyl, optionally substituted
pyridinyl or optionally substituted -phenyl-S(O).sub.2-Z; wherein Z
is CH.sub.3, --N(CH.sub.3).sub.2, optionally substituted
morpholinyl or optionally substituted pyrrolidinyl.
20. A method of treating a condition in a patient comprising
administering a therapeutically effective amount of a compound of
Formula I ##STR00033## pharmaceutically acceptable salts,
biologically active metabolites, solvates, hydrates, pro-drugs,
enantiomers or stereoisomers thereof, wherein X is CH, S or N; Y is
CH, S or N; L is CO, SO, S(O).sub.2 or (C.sub.1-C.sub.4)alkyl; A is
optionally substituted aryl, optionally substituted
(C.sub.3-C.sub.6)cycloalkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl or optionally substituted
-aryl-S(O).sub.2-Z; wherein Z is N(R.sup.5).sub.2, optionally
substituted (C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.3-C.sub.6)cycloalkyl or optionally substituted heterocyclyl;
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently H or
(C.sub.1-C.sub.4)alkyl; and R.sup.5 is independently H,
(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.6)cycloalkyl,
--CO--(C.sub.1-C.sub.6)alkyl, or --CON(R.sup.1).sub.2; provided
that X and Y are not both S, not both CH.sub.2 and not both N; to
said patient in need thereof, wherein the condition is asthma,
allergic asthma, allergic inflammation, rhinitis, allergic rhinitis
or atopic dermatitis.
Description
RELATED APPLICATION
[0001] This application claims priority to and the benefit of U.S.
Provisional Application No. 61/066,046, filed Feb. 15, 2008.
BACKGROUND OF THE INVENTION
[0002] Mast cells are known to play an important role in allergic
and immune responses through the release of a number of mediators,
such as histamine, leukotrienes, cytokines, prostaglandin D2,
etc.
[0003] Prostaglandin D2 (PGD2) is the major metabolite produced by
the action of cyclooxygenase on arachadonic acid by mast cells in
response to allergen challenge (R. A. Lewis et al; J. Immunol.,
1982, 129 (4), 1627) and is also produced by macrophages and Th2
lymphocytes.
[0004] PGD2 has been detected in high concentrations in patients
with systemic mastocytosis (J. L. II Roberts et at; Trans. Ass. Am.
Phys., 1980, 93, 141), allergic rhinitis (R. M. Naclerio et at; Am.
Rev. Respir. Dis., 1983, 128 (4), 597; M. S. Brown et at; Arch.
Otolarynol. Head Neck Surg., 1987, 113 (2), 179; B. Lebel et al; J.
Allergy Clin. Immunol., 1988, 82, 869) and bronchial asthma (J. J.
Murray et at; N. Engl. J. Med., 1986, 315 (13), 800).
[0005] PGD2-driven exaggerated allergic inflammation and
inflammatory responses have been demonstrated in mice and rats.
Transgenic mice over expressing PGD2 synthase exhibit an enhanced
pulmonary eosinophilia and increased levels of Th2 cytokines in
response to allergen challenge (Y. Fujitani et al; J. I;nmunol.,
2002, 168 (1), 443). Also, exogenously administered CRTH2 agonist
13,14-dihydro-15-keto-PGD.sub.2 (DK-PGD.sub.2) enhances the
allergic response in sensitized mice (I. Spik et al; J. Immunol,
2005, 174 (6), 3703). In rats intratracheal administration of CRTH2
agonists causes pulmonary eosinophilia whereas a DP agonist (BW
245C) or a TP agonist (I-BOP) have no effect (Y. Shirashi et al; J.
Pharmacol. Exp. Ther., 2005, 312, 954).
[0006] PGD2 mediates its effects through two high affinity
7-transmembrane receptors, the PGD2 receptor (DP) (Y. Boie et al;
J. Biol. Chem., 1995, 270, 18910) and the chemoattractant
receptor-homologous molecule expressed on Th2 cells (CRTH2) (K.
Nagata et al; J. Immunol, 1999, 162, 1278).
[0007] It has been shown that CRTH2 is expressed on cell types
associated with allergic inflammation, such as Th2 cells, basophils
and eosinophils and that its activation by PGD2 triggers the
migration of these cell types (H. Hirai et at; J. Exp. Med., 2001,
193, 255). CRTH2 was also reported to play a major role in
neutrophil and eosinophil recruitment in a model of contact
dermatitis (K. Takeshita et at; Int. Immunol., 2004, 16,
947-959).
[0008] Allergic asthma and allergic rhinitis are diseases that
currently affect about 10% of the population, and this number
appears to be increasing (R. K. Bush, Handbook of asthma and
rhinitis. 1st ed. (1997), Abingdon: Blackwell Science, 270).
Numerous classes of pharmaceutical agents are widely used to treat
these diseases, for example, antihistamines, decongestants, .beta.2
agonists, anticholinergics, methylxanthines, cromolyns,
corticosteroids, and leukotriene modulators. Generally, the
usefulness of these agents is limited by side effects and low
efficacy. Accordingly, there is a critical medical need to identify
pharmaceutically active compounds that interfere with key steps of
the inflammatory and immunological processes that contribute to
these disease states, and other inflammatory conditions.
[0009] The observations summarized above suggest that CRTH2
antagonists (P. Norman, Exp. Opin. Ther. Patent, 2005, 15(12),
1817) may have valuable properties for the treatment of diseases
mediated by PGD2.
SUMMARY OF THE INVENTION
[0010] In a first embodiment, the invention provides compounds of
Formula I
##STR00002##
pharmaceutically acceptable salts, biologically active metabolites,
solvates, hydrates, pro-drugs, enantiomers or stereoisomers
thereof, wherein
[0011] X is CH, S or N;
[0012] Y is CH, S or N;
[0013] L is CO, SO, S(O).sub.2 or (C.sub.1-C.sub.4)alkyl;
[0014] A is optionally substituted aryl, optionally substituted
(C.sub.3-C.sub.6)cycloalkyl, optionally substituted heteroaryl,
optionally substituted heterocyclyl or optionally substituted
-aryl-S(O).sub.2-Z;
[0015] wherein Z is N(R.sup.5).sub.2, optionally substituted
(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.3-C.sub.6)cycloalkyl or optionally substituted
heterocyclyl;
[0016] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently H or
(C.sub.1-C.sub.4)alkyl; and
[0017] R.sup.5 is independently H, (C.sub.1-C.sub.3)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, --CO--(C.sub.1-C.sub.6)alkyl, or
--CON(R.sup.1).sub.2; provided that X and Y are not both S, not
both CH.sub.2 and not both N at the same time.
[0018] In a second embodiment, the invention provides compounds
according to the first embodiment wherein X is CH.
[0019] In a third embodiment, the invention provides compounds
according to any of the foregoing embodiments wherein Y is S.
[0020] In a fourth embodiment, the invention provides compounds
according to any of the foregoing embodiments wherein L is
S(O).sub.2.
[0021] In a fifth embodiment, the invention provides compounds
according to any of the foregoing embodiments wherein A is
optionally substituted phenyl, optionally substituted naphthyl,
optionally substituted (C.sub.3-C.sub.6)cycloalkyl or optionally
substituted dihydrobenzofuranyl; and
[0022] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently
H.
[0023] In a sixth embodiment, the invention provides compounds
according to any of the foregoing embodiments wherein
[0024] A is optionally substituted phenyl, optionally substituted
dihydrobenzofuranyl or optionally substituted cyclopropyl;
[0025] wherein the phenyl, the dihydrobenzofuranyl or the
cyclopropyl is optionally substituted with one or more substituents
independently selected from halogen, CN, OH,
--SO.sub.2--(C.sub.1-C.sub.6)alkyl,
--SO.sub.2--(C.sub.3-C.sub.6)cycloalkyl,
--O--(C.sub.1-C.sub.4)alkyl and optionally substituted
(C.sub.1-C.sub.6)alkyl.
[0026] In a seventh embodiment, the invention provides compounds
according to the first embodiment wherein X is S.
[0027] In an eighth embodiment, the invention provides compounds
according to the first and seventh embodiments wherein Y is CH.
[0028] In a ninth embodiment, the invention provides compounds
according to the first, seventh and eighth embodiments wherein L is
S(O).sub.2 or (C.sub.1-C.sub.4)alkyl.
[0029] In a tenth embodiment, the invention provides compounds
according to the first and seventh through ninth embodiments
wherein A is optionally substituted aryl, optionally substituted
heteroaryl or optionally substituted -aryl-S(O).sub.2-Z;
[0030] wherein Z is N(R.sup.5).sub.2, optionally substituted
(C.sub.1-C.sub.6)alkyl, optionally substituted
(C.sub.3-C.sub.6)cycloalkyl or optionally substituted heterocyclyl;
and
[0031] R.sup.5 is independently H, (C.sub.1-C.sub.3)alkyl, or
(C.sub.3-C.sub.6)cycloalkyl, --CO--(C.sub.1-C.sub.6)alkyl, or
--CON(R.sup.1).sub.2.
[0032] In an eleventh embodiment, the invention provides compounds
according to the first and seventh through tenth embodiments
wherein R.sup.2 and R.sup.3 are H.
[0033] In a twelfth embodiment, the invention provides compounds
compounds according to the first and seventh through eleventh
embodiments wherein A is optionally substituted isoxazolyl,
optionally substituted naphthyl, optionally substituted phenyl,
optionally substituted pyridinyl or -optionally substituted
phenyl-S(O).sub.2-Z;
[0034] wherein Z is CH.sub.3, --N(CH.sub.3).sub.2,
--N(CH.sub.3)cyclohexyl, optionally substituted morpholinyl or
optionally substituted pyrrolidinyl.
[0035] In a thirteenth embodiment, the invention provides compounds
according to the first and seventh through twelfth embodiments
wherein A is optionally substituted by one or more substituents
independently selected from halogen, CN, CH.sub.3,
--NH--C(O)--CH.sub.3, NHCON(CH.sub.3).sub.2, CF.sub.3,
--S(O).sub.2CH.sub.3, optionally substituted
(C.sub.1-C.sub.4)alkyl, --O--(C.sub.1-C.sub.4)alkyl and
pyrazolyl.
[0036] In a fourteenth embodiment, the invention provides compounds
according to the first and seventh through thirteenth embodiments
wherein R.sup.1 is CH.sub.3 and R.sup.4 is CH.sub.3.
[0037] In a fifteenth embodiment, the invention provides compounds
according to the first and seventh through fourteenth embodiments
wherein R.sup.1 is H and R.sup.4 is H or CH.sub.3.
[0038] In a sixteenth embodiment, the invention provides compounds
according to the first and seventh through fifteenth embodiments
wherein L is CH.sub.2.
[0039] In a seventeenth embodiment, the invention provides
compounds according to the first and seventh through sixteenth
embodiments wherein A is optionally substituted isoxazolyl,
optionally substituted phenyl or optionally substituted
-phenyl-S(O).sub.2-Z;
[0040] wherein Z is CH.sub.3, --N(CH.sub.3).sub.2,
--N(CH.sub.3)cyclohexyl or optionally substituted morpholinyl.
[0041] In an eighteenth embodiment, the invention provides
compounds according to the first and seventh through seventeenth
embodiments wherein L is S(O).sub.2.
[0042] In a nineteenth embodiment, the invention provides compounds
according to the first and seventh through eighteenth embodiments
wherein A is optionally substituted naphthyl, optionally
substituted phenyl, optionally substituted pyridinyl or optionally
substituted -phenyl-S(O).sub.2-Z;
[0043] wherein Z is CH.sub.3, --N(CH.sub.3).sub.2, optionally
substituted morpholinyl or optionally substituted pyrrolidinyl.
[0044] In a twentieth embodiment the invention provides a method of
treating a condition in a patient comprising administering a
therapeutically effective amount of a compound of any of the
foregoing embodiments or a physiologically acceptable salt,
pro-drug or biologically active metabolites thereof to said patient
in need thereof, wherein the condition is asthma, allergic asthma,
allergic inflammation, rhinitis, allergic rhinitis or atopic
dermatitis.
[0045] In a twenty-first embodiment, the compounds of the invention
are useful for the manufacture of medicaments.
DETAILED DESCRIPTION OF THE INVENTION
[0046] The present invention provides compounds of formula (I) or
pharmaceutically acceptable salts thereof that have activity as
pharmaceuticals in the treatment of diseases associated with
elevated PGD.sub.2 levels.
[0047] Compounds of formula (I) or pharmaceutically acceptable
salts thereof are particularly useful as modulators of CRTH2
receptor activity, and may be used in the treatment (therapeutic or
prophylactic) of conditions/diseases which are exacerbated or
caused by excessive or unregulated production of PGD2 and its
metabolites.
[0048] A compound of formula (I), a salt, pro-drug, or
pharmaceutical compositions containing a therapeutically effective
amount thereof can be useful in reducing tissue damage, airway
inflammation, bronchial hyperreactivity, remodeling or disease
progression when used for the treatment of inflammatory or
obstructive airway diseases.
[0049] Inflammatory or obstructive airway diseases that can be
treated with the compounds of the invention include asthma, both
intrinsic (non-allergic) asthma and extrinsic (allergic) asthma,
mild asthma, moderate asthma, severe asthma, bronchitis asthma,
exercise induced asthma, occupational asthma, aspirin induced
asthma, NSAIDs induced asthma and asthma induced following
bacterial infection. In addition, compounds of the invention can
also be useful to treat wheezing symptoms associated with airway
diseases.
[0050] The compounds of the invention are also applicable to the
treatment of other inflammatory or obstructive diseases, such as,
but not limited to, acute lung injury (ALI), adult respiratory
distress syndrome (ARDS), chronic obstructive pulmonary airways or
lung disease (COPD, COAD or COLD), including chronic bronchitis or
dyspnea associated therewith, emphysema, as well as exacerbation of
airway hyperreactivity consequent to other drug therapy, in
particular, other inhaled drug therapy, bronchitis (acute,
arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,
pneumoconiosis (e.g., aluminosis, anthracosis, asbestosis,
chalicosis, ptilosis, siderosis, silicosis, tabacosis and
byssinosis)).
[0051] Eosinophilia and eosinophils-related disorders can also be
treated with the compounds of the invention. Such disorders,
include, but are not limited to, eosinophilic infiltration of
pulmonary tissues, hypereosinophilia, eosinophilic pneumonia,
parasitic infestation including tropical eosinophilia,
bronchopulmonary aspergillosis, polyarteritis nodosa including
Churg-Strauss syndrome, eosinophilic granuloma and
eosinophil-related disorders affecting the airways that can be
caused by drug-reactions.
[0052] Allergic conditions such as those of the skin, e.g.,
psoriasis, contact dermatitis, alopecia areata, erythema
multiforma, dermatitis herpetiformis, scleroderma, vitiligo,
hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus
erythematosus, pemphisus, epidermolysis bullosa acquisita, and
especially atopic dermatitis can also be treated with the compounds
of the invention.
[0053] Other PGD2 mediated diseases that can be prevented or
treated by the compounds of the invention include, but are not
limited to, food allergies, autoimmune diseases such as hyper IgE
syndrome and systemic lupus erythematus, acne, multiple sclerosis,
allographt rejection, reperfusion injury, rheumatoid arthritis,
psoriatic arthritis and osteoarthritis.
[0054] WO 05/102338 describes CRTH2 receptor antagonists for the
treatment of neuropathic pain. Therefore, compounds of the
invention can be of use for the treatment of neuropathic pain.
[0055] Compounds of formula (I) of the invention can be used alone
or in combination with other therapeutic agents to treat such
diseases, e.g., a therapeutic agents being selected by the skilled
artisan for its intended purpose. The co-therapies using the
compounds of this invention with other drug substances can be for
example used to potentiate the therapeutic efficacy of these drugs,
to reduce the dosage of these drugs and possibly their side
effects
[0056] The combinations, which are part of this invention, can be
the compounds of the present invention and at least one additional
agent selected from anti-inflammatory, bronchodilatory,
antihistamine or anti-tussive drug substances. The agents set forth
below are for illustrative purposes and not intended to be
limiting.
[0057] Preferred anti-inflammatory drugs include, but are not
limited to, steroids, in particular, glucocorticosteroids,
budesonide, beclamethasone dipropionate, fluticasone propionate,
ciclesonide or mometasone furoate.
[0058] Preferred bronchodilatory drugs include anticholinergic or
antimuscarinic agents, in particular but not limited to,
ipratropium bromide, oxitropium bromide and tiotropium salts.
[0059] Preferred antihistamine drug substances include, but are not
limited to, cetirizine hydrochloride, clemastine fumarate,
promethazine, loratidine, desloratidine, diphenhydramine and
fexofenadine hydrochloride.
[0060] In addition, combinations of the coumpunds of the invention
with other anti-inflammatory drugs such as chemokine receptors
antagonist drugs, for example , CCR-1, CCR-2, CCR-4, CCR-5, CCR-6,
CCR-7, CCR-8, CCR-9, CCR-10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 ansd
especially CCR-3 antagonists may also be useful.
[0061] In this invention, the following definitions are
applicable:
[0062] A "therapeutically effective amount" is an amount of a
compound of Formula I or a combination of two or more such
compounds, which inhibits, totally or partially, the progression of
the condition or alleviates, at least partially, one or more
symptoms of the condition. A therapeutically effective amount can
also be an amount which is prophylactically effective.
[0063] "Physiologically acceptable salts" refers to those salts
wich retain the biological effectiveness and properties of the free
carboxylic acids, and which are obtained by reaction with
pharmaceutically acceptable bases. Suitable salts include alkali
metal or alkaline earth metal salts including, sodium, potassium,
magnesium, calcium or zinc salts. Other suitable salts are those
obtained by reaction with ammonia or other pharmaceutically
acceptable organic amines or heterocyclic bases, such as, but not
limited to, diethylamine, ethanolamine, diethanolamine,
triethanolamine, ethylenediamine, benethamine, benzathine,
piperazine, tromethamine, 4(2-hydroxyethyl)morpholine,
1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, arginine,
lysine. These salts can be prepared by methods known to the skilled
in the art.
[0064] Certain compounds of formula I and their salts may exist in
more than one crystal form and the present invention includes each
crystal form and mixtures thereof.
[0065] Certain compounds of formula I and their salts may also
exist in the form of solvates, for example hydrates, and the
present invention includes each solvate and mixtures thereof.
[0066] Certain compounds of formula I may contain one or more
chiral centers, and exist in different optically active forms. When
compounds of formula I contain one chiral center, the compounds
exist in two enantiomeric forms and the present invention includes
both enantiomers and mixtures of enantiomers, such as racemic
mixtures.
[0067] When a compound of formula I contains more than one chiral
center, it may exist in diastereoisomeric forms. The present
invention includes each diastereoisomer of compounds of formula I
and mixtures thereof.
[0068] Certain compounds of formula I may exist in different
tautomeric forms or as different geometric isomers, and the present
invention includes each tautomer and/or geometric isomer of
compounds of formula I and mixtures thereof.
[0069] Certain compounds of formula I may exist in different stable
conformational forms which may be separable. Torsional asymmetry
due to restricted rotation about an asymmetric single bond, for
example because of steric hindrance or ring strain, may permit
separation of different conformers. The present invention includes
each conformational isomer of compounds of formula I and mixtures
thereof and in particular geometric isomers when R.sup.1 and
R.sup.2 are not both H.
[0070] Certain compounds of formula I may exist in zwitterionic
form and the present invention includes each zwitterionic form of
compounds of formula I and mixtures thereof. As used herein the
term "pro-drug" refers to an agent which is converted into the
parent drug in vivo by some physiological chemical process (e.g., a
pro-drug on being brought to the physiological pH is converted to
the desired drug form). Pro-drugs are often useful, for example
they may be easier to administer than the parent drug or offer
better oral bioavailability than the parent drug. An example,
without limitation, of a pro-drug would be a compound of the
present invention wherein it is administered as an hydrolizable
ester (the "pro-drug"). Such hydrolyzable esters include but are
not limited to the carboxylic acids wherein the free hydrogen is
replaced by (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl,
(C.sub.4-C.sub.9)1-(alkanoyloxy)ethyl,
1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,
1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,
1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon
atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon
atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)-alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0071] The term "heterocyclic" or "heterocyclyl", as used herein,
include non-aromatic, ring systems, including, but not limited to,
monocyclic, bicyclic and tricyclic rings, which can be completely
saturated or which can contain one or more units of unsaturation
(for the avoidance of doubt, the degree of unsaturation does not
result in an aromatic ring system and have 3 to 12 atoms including
at least one heteroatom, such as nitrogen, oxygen, or sulfur). For
purposes of exemplification, which should not be construed as
limiting the scope of this invention, the following are examples of
heterocyclic rings: azepines, azetidinyl, morpholinyl,
oxopiperidinyl, oxopyrrolidinesyl, piperazinyl, piperidinyl,
pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl and
tetrahydrofuranyl.
[0072] The term "heteroaryl" as used herein, include aromatic ring
systems, including, but not limited to, monocyclic, bicyclic and
tricyclic rings, and have 3 to 12 atoms including at least one
heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of
exemplification, which should not be construed as limiting the
scope of this invention: azaindolyl, benzo(b)thienyl,
benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl,
benzothiadiazolyl, benzoxadiazolyl, furanyl, imidazolyl,
imidazopyridinyl, indolyl, indolinyl, indazoles, isoindolinyl,
isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, purinyl, pyranyl,
pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl,
pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, quinolinyl,
quinazolinyl, thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl,
thiadiazolyl, thienyl, thiomorpholinyl, triazolyl or tropanyl.
[0073] When the term "substituted heterocyclic" (or heterocyclyl)
or "substituted heteroaryl" is used, what is meant is that the
heterocyclic group is substituted with one or more substituents
that can be made by one of ordinary skill in the art and results in
a molecule that is a CRTH2 antagonist. For purposes of
exemplification, which should not be construed as limiting the
scope of this invention, preferred substituents for the heterocycle
of this invention are each independently selected from the
optionally substituted group consisting of alkenyl, alkoxy,
alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylheterocycloalkoxy, alkyl, alkylcarbonyl, alkylester,
alkyl-O--C(O)--, alkyl-heterocyclyl, alkyl-cycloalkyl,
alkyl-nitrile, alkynyl, amido groups, amino, aminoalkyl,
aminocarbonyl, carbonylalkoxy, carboxamido, CF.sub.3, CN, --C(O)H,
--C(O)--C(CH.sub.3).sub.3, --OH, --C(O)-cycloalkyl,
--C(O)-heterocyclyl, cycloalkyl, dialkylaminoalkoxy,
dialkylaminocarbonylalkoxy, dialkylaminocarbonyl, halogen,
heterocyclyl, a heterocycloalkyl group, heterocyclyloxy,
hydroxyalkyl, nitro, OCF.sub.3, oxo, phenyl, --SO.sub.2CH.sub.3,
--SO.sub.2CR.sub.3, tetrazolyl, thienylalkoxy,
trifluoromethylcarbonylamino, trifluoromethylsulfonamido,
heterocyclylalkoxy, heterocyclyl-S(O).sub.p, cycloalkyl-S(O).sub.p,
alkyl-S--, heterocyclyl-S, heterocycloalkyl, cycloalkylalkyl,
heterocycolthio, cycloalkylthio, -Z.sup.105-C(O)N(R).sub.2,
-Z.sup.105-N(R)--C(O)-Z.sup.200,
-Z.sup.105-N(R)--S(O).sub.2-Z.sup.200,
-Z.sup.105-N(R)--C(O)--N(R)-Z.sup.200,
-Z.sup.105-S(O).sub.p--N(R)-Z.sup.200, --N(R)--C(O)R,
--OR--C(O)-heterocyclyl-OR, R.sub.c and --CH.sub.2OR.sub.c;
[0074] wherein R.sub.3 is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6
cycloalkyl or phenyl;
[0075] wherein p is 0, 1 or 2;
[0076] where R.sub.c for each occurrence is independently hydrogen,
optionally substituted alkyl, optionally substituted aryl,
--(C.sub.1-C.sub.6)-NR.sub.dR.sub.e,
-E-(CH.sub.2).sub.t--NR.sub.dR.sub.e, -E-(CH.sub.2).sub.t--O-alkyl,
-E-(CH.sub.2).sub.t--S-alkyl, or -E-(CH.sub.2).sub.t--OH;
[0077] wherein t is an integer from about 1 to about 6;
[0078] Z.sup.105 for each occurrence is independently a covalent
bond, alkyl, alkenyl or alkynyl; and
[0079] Z.sup.200 for each occurrence is independently selected from
an optionally substituted group selected from the group consisting
of alkyl, alkenyl, alkynyl, phenyl, alkyl-phenyl, alkenyl-phenyl or
alkynyl-phenyl;
[0080] E is a direct bond, O, S, S(O), S(O).sub.2, or NR.sub.f,
wherein R.sub.f is H or alkyl and R.sub.d and R.sub.e are
independently H, alkyl, alkanoyl or SO.sub.2-alkyl; or R.sub.d,
R.sub.e and the nitrogen atom to which they are attached together
to form a five- or six-membered heterocyclic ring.
[0081] As used herein, "aliphatic" or "an aliphatic group" or
notations such as "(C.sub.0-C.sub.8)" include straight chained or
branched hydrocarbons which are completely saturated or which
contain one or more units of unsaturation, and, thus, includes
alkyl, alkenyl, alkynyl and hydrocarbons comprising a mixture of
single, double and triple bonds. When the group is a C.sub.0 it
means that the moiety is not present or in other words, it is a
bond. As used herein, "alkyl" means C.sub.1-C.sub.8 and includes
straight chained or branched hydrocarbons, which are completely
saturated. Preferred alkyls are methyl, ethyl, propyl, butyl,
pentyl, hexyl and isomers thereof. As used herein, "alkenyl" and
"alkynyl" means C.sub.2-C.sub.8 and includes straight chained or
branched hydrocarbons which contain one or more units of
unsaturation, one or more double bonds for alkenyl and one or more
triple bonds for alkynyl.
[0082] As used herein, aromatic groups (or aryl groups) include
aromatic carbocyclic ring systems (e.g. phenyl and
cyclopentyldienyl) and fused polycyclic aromatic ring systems (e.g.
naphthyl, biphenylenyl and 1,2,3,4-tetrahydronaphthyl).
[0083] As used herein, cycloalkyl means C.sub.3-C.sub.12 monocyclic
or multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbons that
is completely saturated or has one or more unsaturated bonds but
does not amount to an aromatic group. Preferred examples of a
cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl and cyclohexenyl.
[0084] As used herein, many moieties or substituents are termed as
being either "substituted" or "optionally substituted". When a
moiety is modified by one of these terms, unless otherwise noted,
it denotes that any portion of the moiety that is known to one
skilled in the art as being available for substitution can be
substituted, which includes one or more substituents, where if more
than one substituent then each substituent is independently
selected. Such means for substitution are well-known in the art
and/or taught by the instant disclosure. For purposes of
exemplification, which should not be construed as limiting the
scope of this invention, some examples of groups that are
substituents are: alkenyl groups, alkoxy group (which itself can be
substituted, such as --O--C.sub.1-C.sub.6-alkyl-OR,
--O--C.sub.1-C.sub.6-alkyl-N(R).sub.2, and OCF.sub.3),
alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylpiperidinyl-alkoxy,
alkyl groups (which itself can also be substituted, such as
--C.sub.1-C.sub.6-alkyl-OR, --C.sub.1-C.sub.6-alkyl-N(R).sub.2, and
--CF.sub.3), alkylamino, alkylcarbonyl, alkylester, alkylnitrile,
alkylsulfonyl, amino, aminoalkoxy, CF.sub.3, COH, COOH, CN,
cycloalkyl, dialkylamino, dialkylaminoalkoxy, dialkylaminocarbonyl,
dialkylaminocarbonylalkoxy, dialkylaminosulfonyl, where R is groups
such as alkyl, heterocycloalkyl (which can be substituted),
heterocyclyl, etc., which can be substituted), halogen or halo
group (F, Cl, Br, I), hydroxy, morpholinoalkoxy, morpholinoalkyl,
nitro, oxo, OCF.sub.3, optionally substituted phenyl,
--S(O).sub.2(C.sub.1-C.sub.4)alkyl, --S(O).sub.2CF.sub.3,
--S(O).sub.2cycloalkyl, --S(O).sub.2NR'R'' where R' and R'' are
independently H, alkyl or heterocyclyl, sulfonyl, N-alkylamino or
N,N-dialkylamino (in which the alkyl groups can also be
substituted).
[0085] One or more compounds of this invention can be administered
to a human patient by themselves or in pharmaceutical compositions
where they are mixed with biologically suitable carriers or
excipient(s) at doses to treat or ameliorate a disease or condition
as described herein. Mixtures of these compounds can also be
administered to the patient as a simple mixture or in suitable
formulated pharmaceutical compositions. A therapeutically effective
dose refers to that amount of the compound or compounds sufficient
to result in the prevention or attenuation of a disease or
condition as described herein. Techniques for formulation and
administration of the compounds of the instant application may be
found in references well known to one of ordinary skill in the art,
such as "Remington's Pharmaceutical Sciences," Mack Publishing Co.,
Easton, Pa., latest edition.
[0086] Suitable routes of administration for the compounds of the
invention may, for example, include oral administration, e.g., in
the form of tablets, capsules or drageas, inhalation, intranasal
administration, topical administration, intravenous injection,
eyedrops, rectal and transmucosal administration.
[0087] The teachings of all references, including journal articles,
patents and published patent applications, are incorporated herein
by reference in their entirety.
Enzyme Assays
Radioligand Binding Assay
[0088] Binding was performed on membranes prepared from HEK293.F
cells (Invitrogen) transiently transfected with human CRTH2 cDNA.
Assays were performed in a final volume of 100 .mu.L of assay
buffer (50 m HEPES pH 7.0, 10 mM MnCl.sub.2, 1 mM EDTA, 0.2% BSA)
in a 96-well round-bottom polypropylene plate (Costar 3357).
Compounds were serially diluted in 100% DMSO then diluted into 10%
DMSO/assay buffer before addition of 10 .mu.l to the assay plate
(Final DMSO conc. in assay is 1% (v/v)). 40 .mu.L of CRTH2
membranes (20 ug/well) was added to each well and incubated at room
temperature for 10 min. 50 .mu.L of [.sup.3H]-PGD.sub.2
(PerkinElmer NET-616, 171 Ci/mmol) was added to each well (Final
conc. 1 nM) and incubated at room temperature for 1 hour. Total and
non-specific binding was determined in absence and presence of 10
.mu.M unlabeled PGD.sub.2. Assay plates were harvested (PerkinElmer
Filtermate Harvester) onto a GF/C filter plate (pre-soaked in 0.3%
(v/v) polyethyleneimine) and washed with 5 well volumes of cold
wash buffer (50 mM HEPES pH 7.0, 500 mM NaCl). Plates were dried
for 1 hour in a vacuum oven, 50 .mu.L of Microscint-20 added to
each well and bound radioactivity quantified by scintillation
counting (PerkinElmer Topcount NXT HTS). IC.sub.50s were determined
by non-linear regression using the following four-parameter
logistic equation:
Y=Bottom+(Top-Bottom)/(1+10.LAMBDA.((Log
IC.sub.50-X)*Hillslope)
[0089] where Y denotes specific binding, X is logarithmic
concentration of antagonist, top is total binding and bottom is
non-specific binding.
[0090] Compounds of the invention may be prepared using the
synthetic transformations illustrated in Schemes I-IV. Starting
materials are commercially available or may be prepared by the
procedures described herein, by literature procedures, or by
procedures that would be well known to one skilled in the art of
organic chemistry.
[0091] Methods for preparing thienopyrroles 4 and 5 of the
invention are illustrated in Scheme I. Unsubstituted thienopyrrole
ethyl ester 1 (R.sup.1.dbd.R.sup.2.dbd.R.sup.3.dbd.H; R.sup.4=Et)
is prepared from the tert-butyl 3-iodothiophen-2-ylcarbamate as
described by Wensbo D., Annby U. and Gronowitz S. in Tetrahedron,
1995, 51(37), 10323.
[0092] A suitably substituted thienopyrrole ester 1 may be reacted
in a number of ways. For example, reaction with a sulfonyl chloride
or a benzyl halide using General Procedures A and B respectively
yield esters 2 and 3. Subsequent saponification of the ester group
can be performed using conditions known in the literature (see
Greene, T. W. and Wuts, P. G. M. "Protective Groups in Organic
Synthesis, 3.sup.rd Edition", 1999, Wiley-Interscience, or General
Procedure C and D) to afford thienopyrroles 4 and 5.
##STR00003##
[0093] As shown in Scheme II, substituted thienopyrrole esters 1
are synthesized from the tert-butyl 3-halothiophen-2-ylcarbamates
9, via a "one-pot two step sequence" involving an alkylation with
crotonate 12 followed by an intramolecular Heck coupling using
conditions described in General Procedure H to give Boc-protected
intermediate 13 that is deprotected using methods known in the
literature (see Greene, T. W. and Wuts, P. G. M. "Protective Groups
in Organic Synthesis, 3.sup.rd Edition", 1999, Wiley-Interscience,
or General Procedure I). The tert-butyl
3-halothiophen-2-ylcarbamates 9 can be prepared from commercially
available thiophene-2-carboxylates 6 (R.sup.4.dbd.H, R.sup.3=alkyl)
or 3-halothiophene-2-carboxylic acids 10 (R.sup.4=halogen,
R.sup.3.dbd.H). For example, a thiophene-2-carboxylate 6
(R.sup.4.dbd.H) can be saponified to the corresponding
thiophene-2-carboxylic acid 7 (R.sup.4.dbd.H) using conditions
known in the literature (see Greene, T. W. and Wuts, P. G. M.
"Protective Groups in Organic Synthesis, 3.sup.rd Edition", 1999,
Wiley-Interscience, or General Procedure E). Acid 7 (R.sup.4.dbd.H)
can be subjected to a Curtius rearrangement using methods known to
one skilled in the art (see, for example, Y. Yang, A.-B. Hornfeldt,
S. Gronowitz, Chemica Scripta, 1998, 28, 275 or General Procedure
F). The resulting tert-butyl thiophen-2-ylcarbamates 8
(R.sup.4.dbd.H) can be halogenated using methods known to one
skilled in the art (see, for example, Larock, R. C. "Comprehensive
Organic Transformations: A Guide to Functional Group Preparations,
2.sup.nd edition", 1999, Wiley-VCH ) and in particular brominated,
with bromine, to give the tert-butyl 3-bromothiophen-2-ylcarbamates
9 (Hal=Br) using General Procedures G.
[0094] Similarly, 3-halothiophene-2-carboxylates 10
(R.sup.4=halogen, R.sup.3=alkyl) can be converted to tert-butyl
3-halothiophen-2-ylcarbamates 9 with a sequence of saponification
using General Procedures E to give 11 (R.sup.4=halogen) and Curtius
Rearrangement using General Procedure F.
##STR00004##
##STR00005##
[0095] Non commercially available
4-(bromomethyl)benzenesulfonamides to be used in General Procedure
B of Scheme I can be prepared using methods known to one skilled in
the art (see, for example, Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations, 2.sup.nd
edition", 1999, Wiley-VCH).
[0096] For example, 4-(bromomethyl)benzenesulfonamides 15 can be
synthesized by reacting the 4-(bromomethyl)benzene-1-sulfonyl
chloride 14 and an amine using General Procedure J, as shown in
Scheme III.
##STR00006##
[0097] The preparation of thienopyrroles 18 of the invention is
illustrated in Scheme IV. The unsubstituted thienopyrrole ethyl
ester 16 (R.sup.1.dbd.R.sup.2.dbd.R.sup.3.dbd.H; R.sup.4=Et) is
prepared from the tert-butyl 2-iodothiophen-3-ylcarbamate as
described by Wensbo D., Annby U. and Gronowitz S. in tetrahedron,
1995, 51(37), 10323.
[0098] Substituted thienopyrrole esters 16 can be synthesized from
tert-butyl 2-iodo- or tert-butyl 2-bromo-thiophen-3-ylcarbamates,
using the same sequence as that described in Scheme I, via a
"one-pot two step sequence" involving an alkylation with a
crotonate 12 followed by an intramolecular Heck coupling using
conditions described in General Procedure H and a Boc-deprotection
using General Procedure I.
[0099] A suitably substituted ethyl
2-(5-methyl-4H-thieno[3,2-b]pyrrol-6-yl)acetate 16 can be further
reacted in a number of ways.
[0100] For example, reaction with a sulfonyl chloride using General
Procedure K yields ester 17. Saponification of the ester group in
17 can be performed using conditions known in the literature (see
Greene, T. W. and Wuts, P. G. M. "Protective Groups in Organic
Synthesis, 3.sup.rd Edition", 1999, Wiley-Interscience, or General
Procedure L) to afford thienopyrroles 18.
Abbreviations
[0101] ACN Acetonitrile [0102] Boc tert-Butoxycarbonyl [0103] DCE
Dichloroethane [0104] DCM Dichloromethane (methylene chloride)
[0105] DIPEA N,N-Diisopropylethylamine [0106] DMA
N,N-Dimethylacetamide [0107] DMAP 4-(Dimethylamino)pyridine [0108]
DME 1,2-Dimethoxyethane [0109] DMF N,N-Dimethylformamide [0110]
DMSO Dimethyl sulfoxide [0111] equiv Equivalent (molar equivalent)
[0112] EtOAc Ethyl acetate [0113] EtOH Ethyl alcohol [0114]
Et.sub.2O Diethyl ether [0115] HOAc Acetic acid [0116] HPLC
High-pressure liquid chromatography [0117] IPA Isopropyl alcohol
[0118] LC/MS Liquid chromatography/mass spectrometry [0119] M Molar
[0120] MeOH Methyl alcohol [0121] N Normal [0122] NIS
N-Iodosuccinimide [0123] NMR Nuclear magnetic resonance [0124]
n-PrOH n-Propyl alcohol [0125] PPh.sub.3 Triphenylphosphine [0126]
RP-HPLC Reverse-phase high-pressure liquid chromatography [0127]
R.sub.f Retention factor [0128] R.sub.t Retention time [0129] TEA
Triethylamine [0130] TFA Trifluoroacetic acid [0131] THF
Tetrahydrofuran [0132] TLC Thin layer chromatography [0133] UV
Ultraviolet light [0134] wt % Weight percent
GENERAL PROCEDURES AND EXAMPLES
[0135] The general synthetic schemes that were utilized to
construct the majority of compounds disclosed in this application
are described below in Schemes 1-16. These schemes are provided for
illustrative purposes only and are not to be construed as limiting
the scope of the invention.
##STR00007##
##STR00008##
##STR00009##
##STR00010##
##STR00011##
##STR00012##
##STR00013##
##STR00014##
##STR00015##
##STR00016##
##STR00017##
##STR00018##
List of General Procedures
TABLE-US-00001 [0136] General Procedure A Coupling of a
2-(6H-thieno[2,3-b]pyrrol-4-yl)acetate with sulfonylchlorides
General Procedure B Coupling of a
2-(6H-thieno[2,3-b]pyrrol-4-yl)acetate with benzylhalides General
Procedure C Saponification of a
2-(6-(sulfonyl)-6H-thieno[2,3-b]pyrrol-4- yl)acetate General
Procedure D Saponification of a
2-(6-benzyl-6H-thieno[2,3-b]pyrrol-4- yl)acetate General Procedure
E Saponification of a thiophene-2-carboxylate General Procedure F
Formation of a tert-butyl thiophen-2-ylcarbamate General Procedure
G Bromination of a tert-butyl thiophen-2-ylcarbamate General
Procedure H One pot alkylation/cyclization to a tert-butyl
6H-thieno[2,3- b]pyrrole-6-carboxylate General Procedure I
Deprotection of a tert-butyl 6H-thieno[2,3-b]pyrrole-6- carboxylate
General Procedure J Preparation of
4-(halomethyl)benzenesulfonamides General Procedure K Coupling of a
4H-thieno[3,2-b]pyrrole with sulfonylchlorides General Procedure L
Saponification of a
2-(4-(sulfonyl)-4H-thieno[3,2-b]pyrrol-6-yl)acetate
[0137] The synthetic routes to any novel intermediates are detailed
by sequentially listing the general procedure (letter codes) in
parentheses after their name. A worked example of this protocol is
given below using Example #D.1.1 as a non-limiting illustration.
Example #D.1.1 is the
5-methyl-6-(4-(methylsulfonyl)benzyl)-6H-thieno[2,3-b]pyrrol-4-yl)acetic
acid which was prepared from the methyl
2-(5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate using General
Procedure B and General Procedure D, as represented in the
following synthetic scheme:
##STR00019##
[0138] The precursor to Example #D.1.1, the methyl
2-(5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate, was prepared by
the noted reaction sequence: using General Procedure F from the
3-bromothiophene-2-carboxylic acid with diphenylphosphoryl azide in
tert-butanol, General Procedure H with the (E)-methyl
4-bromopent-2-enoate (prepared according to C. Girard, I. Romain,
M. Ahmar and R. Bloch, Tetrahedron Letters, 1989, 30 (52), 7275),
K.sub.2CO.sub.3, triphenylphosphine and palladium acetate, and
finally deprotected by heating under vacuum according to General
Procedure I, which translates to the following synthetic
scheme:
##STR00020##
[0139] The general synthetic methods used in each general procedure
follow and include an illustration of a compound that was
synthesized using the designated general procedure. None of the
specific conditions and reagents noted in the following are to be
construed as limiting the scope of the invention and are provided
for illustrative purposes only. All starting materials are
commercially available from Sigma-Aldrich unless otherwise noted
after the chemical name. Analytical data is included either in the
illustrations of the general procedures or in the tables of
examples. Unless otherwise stated, all .sup.1H NMR data were
collected on a Varian Mercury Plus 400 MHz instrument; chemical
shifts are quoted in parts per million (ppm). LC/MS and HPLC data
is referenced to the table of LC/MS and HPLC conditions using the
lower case method letter in parentheses provided in Table 1.
TABLE-US-00002 TABLE 1 LC/MS and HPLC methods Method Conditions a
LC/MS: The column used for the chromatography was a 50 .times. 4.6
mm Zorbax XDB C18 column (5 .mu.m particles). The gradient was
5-95% B in 3.7 min with a hold at 95% B for 1 min (1.3 mL/min flow
rate). Mobile phase A was 10 mM ammonium acetate and mobile phase B
was HPLC grade acetonitrile. Detection methods are diode array
(DAD) and evaporative light scattering (ELSD) detection as well as
positive/negative electrospray ionization b LC/MS: The column used
for the chromatography was a 50 .times. 4.6 mm Zorbax XDB C18
column (5 .mu.m particles). The gradient was 5-95% B in 3.7 min
with a hold at 95% B for 1 min (1.3 mL/min flow rate). Mobile phase
A was 10 mM ammonium acetate, mobile phase B was HPLC grade
acetonitrile. Detection methods are diode array (DAD) and
evaporative light scattering (ELSD) detection as well as pos/neg
atmospheric pressure chemical ionization (APCI). c LC/MS: The
column used for the chromatography was a 4.6 .times. 30 mm Vydac
Genesis C8 column (4 .mu.m particles). The gradient was 5-60% B in
1.5 min then 60-95% B to 2.5 min with a hold at 95% B for 1.2 min
(1.3 mL/min flow rate). Mobile phase A was 10 mM ammonium acetate
and mobile phase B was HPLC grade acetonitrile. Detection methods
are diode array (DAD) and evaporative light scattering (ELSD)
detection as well as positive/negative electrospray ionization. d
LC/MS: The column used for the chromatography was a 4.6 .times. 30
mm Vydac Genesis C8 column (4 .mu.m particles). The gradient was
30-95% B in 2 min then hold at 95% B to 5.7 min (1.0 mL/min flow
rate). Mobile phase A was 10 mM ammonium acetate and mobile phase B
was HPLC grade acetonitrile. Detection methods are diode array
(DAD) and evaporative light scattering (ELSD) detection as well as
positive/negative electrospray ionization. e LC-MS: Using a Waters
ZMD mass spectrometer and Alliance HPLC system running MassLynx 3.4
and Openlynx 3.4 software. The ZMD mass spectrometer was operated
under positive APCI ionization conditions. The HPLC system
comprised a Waters 2795 autosampler sampling from 96-well plates, a
Waters 996 diode-array detector and Sedere Sedex-75 evaporative
light scattering detector. The column used was a Phenomenex Luna
Combi-HTS C8(2) 5 .mu.m 100.ANG. (2.1 mm .times. 30 mm). A gradient
of 10-100% acetonitrile (A) and 0.1% trifluoroacetic acid in water
(B) was used, at a flow rate of 1.5 mL/min (0-0.1 min 10% A,
0.1-3.1 min 10-100% A, 3.1-3.9 min 100-10% A, 3.9-4.0 min 100-10%
A). f HPLC: The column used for the chromatography was a 21.2
.times. 250 mm Hypersil C18 HS column (8 .mu.m particles). The
gradient was 15-100% B over 25 min (21 mL/min flow rate). Mobile
phase A was 0.05 N aqueous ammonium acetate buffer (pH 4.5) and
mobile phase B was HPLC grade acetonitrile. Detection method is UV,
.lamda. = 254 nm. g HPLC: The column used for the chromatography
was a 21.2 .times. 250 mm Hypersil C18 HS column (8 .mu.m
particles). The gradient was 0-80% B over 50 min (21 mL/min flow
rate). Mobile phase A was 0.05 N aqueous ammonium acetate buffer
(pH 4.5) and mobile phase B was HPLC grade acetonitrile. Detection
method is UV, .lamda. = 254 nm. h HPLC: The column used for the
chromatography was a 21.2 .times. 250 mm Hypersil C18 HS column (8
.mu.m particles). The gradient was 5-95% B over 25 min (21 mL/min
flow rate). Mobile phase A was 0.05N aqueous ammonium acetate
buffer (pH 4.5) and mobile phase B was HPLC grade acetonitrile.
Detection method is UV, .lamda. = 254 nm. g HPLC: The column used
for the chromatography was a 21.2 .times. 250 mm Hypersil C18 HS
column (8 .mu.m particles). The gradient was 5-100% B over 25 min
(21 mL/min flow rate). Mobile phase A was 0.05N aqueous ammonium
acetate buffer (pH 4.5) and mobile phase B was HPLC grade
acetonitrile. Detection method is UV, .lamda. = 254 nm. h HPLC on a
Waters Nova-Pak .RTM. HR C18 6um 60 .ANG. Prep-Pak .RTM. cartridge
column (25 mm .times. 100 mm). A gradient of acetonitrile (A) and
0.1% trifluoroacetic acid in water (B) was used, at a flow rate of
40 mL/min (0-0.5 min 10% A, 0.5-6.0 min linear gradient 10-100% A,
6.0-7.0 min 100% A, 7.0-8.0 min linear gradient 100-10% A). Samples
were injected in 1.5 mL DMSO:MeOH (1:1). An Agilent 1100 Series
Purification system was used, consisting of the following modules:
Agilent 1100 Series LC/MSD SL mass spectrometer with
API-electrospray source; two Agilent 1100 Series preparative pumps;
Agilent 1100 Series isocratic pump; Agilent 1100 Series diode array
detector with preparative (0.3 mm) flow cell; Agilent 35900E
multichannel interface; LC-Packings Acurate 1: 1000 flow-splitter;
Gilson 215 liquid- handler with 819 Injector fitted with a 2 mL
loop; and Sedere Sedex-55 evaporative light scattering detector
(ELSD). The make-up pump for the mass spectrometer used 3:1
methanol:water with 0.1% formic acid at a flow rate of 1 mL/min. A
tee downstream of the flow-splitter divided the flow between ELSD
and MS detectors with 0.45 mL/min flow to the MS. Fraction
collection was automatically triggered when the extracted ion
chromatogram (EIC) for the target mass exceeded the threshold
specified in the method. The system was controlled using Agilent
Chemstation (Rev A.08.04) and Integ CC-Mode (Rev A.03.02) software,
with custom Chemstation macros for data export
General Procedure A: Coupling of a
2-(6H-thieno[2,3-b]pyrrol-4-yl)acetate with sulfonylchlorides
[0140] To a solution of alkyl
2-(6H-thieno[2,3-b]pyrrol-4-yl)acetate (such as methyl, ethyl or
tert-butyl, preferably methyl
2-(6H-thieno[2,3-b]pyrrol-4-yl)acetate) (preferably 1 equiv) in an
organic solvent (such as THF or dioxane, preferably THF) at about
-5.degree. C. to 25.degree. C. (preferably 0.degree. C.) is added a
base (such as potassium tBuOK, tBuONa, NaOEt, NaOMe, preferably
tBuOK) (1-2 equiv, preferably 1.4 equiv), followed by a sulfonyl
chloride (1-1.5 equiv, preferably 1.2 equiv). The reaction mixture
is stirred at ambient temperature for about 30 min-2 h (preferably
1 h) to give the crude
2-(6-(sulfonyl)-6H-thieno[2,3-b]pyrrol-4-yl)acetate, which can be
used in subsequent reactions without further purification.
Illustration of General Procedure
Preparation #A.1: Methyl
2-(5-methyl-6-(4-(methylsulfonyl)phenylsulfonyl)-6H-thieno[2,3-b]pyrrol-4-
-yl)acetate
##STR00021##
[0142] To a solution of methyl
2-(5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate (0.059 g, 0.282
mmol) in THF at about 0.degree. C. was added tBuOK (0.044 g, 0.395
mmol), followed by the 4-(methylsulfonyl)-benzene-1-sulfonyl
chloride (0.086 g, 0.338 mmol). The reaction mixture was stirred at
ambient temperature for about 1 h to give the crude title compound,
which was used without further purification. LC/MS (Table 1, Method
b) R.sub.t=2.25 min; MS m/z 428 (M+H).sup.+.
General Procedure B: Coupling of a
2-(6H-thieno[2,3-b]pyrrol-4-yl)acetate with benzylhalides
[0143] Sodium hydride (1-2 equiv, preferably 1.12 equiv) is added
to a solution of alkyl 2-(6H-thieno[2,3-b]pyrrol-4-yl)acetate (such
as methyl, ethyl or tert-butyl, preferably methyl
2-(6H-thieno[2,3-b]pyrrol-4-yl)acetate) (preferably 1 equiv) in an
organic solvent (such as DMF, THF or dioxane, preferably DMF) at
about 0-10.degree. C. (preferably about 0.degree. C.). The mixture
is stirred at about 0-10.degree. C. (preferably about 0.degree. C.)
for about 1-5 h (preferably about 1 h) before sequential addition
of a benzyl halide (1-2 equiv, preferably 1.2 equiv) and sodium
iodide (1-2 equiv, preferably 1.2 equiv). The resulting reaction
mixture is allowed to warm up to ambient temperature over about
2-10 h (preferably 4 h). The crude mixture is diluted with an
organic solvent (such as EtOAc, DCM or Et.sub.2O, preferably EtOAc)
and washed with water. The layers are separated and the organic
solution is dried over a drying agent (such as Na.sub.2SO.sub.4 or
MgSO.sub.4, preferably MgSO.sub.4), filtered and concentrated under
reduced pressure to give the target compound, which can optionally
be purified by chromatography on silica gel.
Illustration of General Procedure B
Preparation #B.1: Methyl
2-(5-methyl-6-(4-(methylsulfonyl)benzyl)-6H-thieno[2,3-b]pyrrol-4-yl)acet-
ate
##STR00022##
[0145] Sodium hydride (0.014 g, 0.583 mmol) was added to a solution
of methyl 2-(5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate (0.109 g,
0.52 mmol) in DMF (5 mL) at 0.degree. C. The mixture was stirred 1
h at 0.degree. C. before sequential addition of the
1-(chloromethyl)-4-(methylsulfonyl)benzene (0.156 g, 0.762 mmol)
and sodium iodide (0.0935 g, 0.624 mmol). The reaction mixture was
allowed to warm up to ambient temperature over 4 h. EtOAc was added
and the resulting solution washed with water. The layers were
separated and the organic solution was dried over MgSO.sub.4,
filtered and concentrated under reduced pressure. The crude
material was purified by chromatography on silica gel
(heptane/EtOAc: 80/20 to 50/50) to give the title compound (0.117
g, 59.6%): LC/MS (Table 1, Method b) R.sub.t=2.45 min; MS m/z 395
(M+NH.sub.4).sup.+.
General Procedure C: Saponification of a
2-(6-(sulfonyl)-6H-thieno[2,3-b]pyrrol-4-yl)acetate
[0146] To a 2-(6-(sulfonyl)-6H-thieno[2,3-b]pyrrol-4-yl)acetate (1
equiv) in an organic solvent (such as THF or dioxane, preferably
THF) is added an alcohol (such as MeOH or EtOH, preferably EtOH)
(20-50 equiv, preferably 40 equiv) and water, followed by a base
(such as NaOH, KOH or LiOH preferably KOH) (2-5 equiv, preferably 3
equiv). The reaction mixture is stirred at ambient temperature for
about 10 min-4 h (preferably 2 h). An acid (such as HCOOH, TFA,
AcOH, preferably AcOH) (2-5 equiv, preferably 3 equiv) is added.
The reaction mixture is dried under reduced pressure (Genevac.RTM.)
and the residue purified by preparative HPLC.
Illustration of General Procedure C
Example C.1.1:
2-(5-Methyl-6-(4-(methylsulfonyl)phenylsulfonyl)-6H-thieno[2,3-b]pyrrol-4-
-yl)acetic acid
##STR00023##
[0148] Methanol (0.5 mL) and water (0.5 mL) were added to the crude
methyl
2-(5-methyl-6-(4-(methylsulfonyl)phenylsulfonyl)-6H-thieno[2,3-b]pyrrol-4-
-yl)acetate, followed by the addition of KOH (47.5 mg, 0.846 mmol).
The mixture was stirred at ambient temperature for 1 h before
adding the AcOH (0.66 mL). The reaction mixture was dried under
reduced pressure (Genevac.RTM.) and the residue purified by HPLC
(Table 1, Method g) to afford the title compound (0.017 g, 14.6%):
LC/MS (Table 1, Method b) R.sub.t=1.89 min; MS m/z 412 (M-H).sup.-;
.sup.1H NMR (DMSO) .delta. 8.19-8.08 (m, 4H), 7.23 (d, 1H, J=5.28
Hz), 6.96 (d, 1H, J=5.28 Hz), 3.41 (s, 2H), 3.29 (s, 3H), 2.37 (s,
3H).
TABLE-US-00003 TABLE C.1 Examples of
2-(6-sulfonyl-5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetic acids
General Procedure C R.sub.t min Ester Product Example # (method)
m/z ESI Methyl 2-(5-methyl-6- 2-(5-Methyl-6- C.1.2 2.03 (b) 336.1
(M + H).sup.+ (phenylsulfonyl)-6H-thieno[2,3- (phenylsulfonyl)-6H-
b]pyrrol-4-yl)acetate [prepared thieno[2,3-b]pyrrol-4- using A from
the methyl 2-(5- yl)acetic acid methyl-6H-thieno[2,3-b]pyrrol-4-
yl)acetate and the benzenesulfonyl chloride] Methyl 2-(5-methyl-6-
2-(6-(4- C.1.3 2.07 (b) 370.0 (M + H).sup.+
(phenylsulfonyl)-6H-thieno[2,3- Chlorophenylsulfonyl)-5-
b]pyrrol-4-yl)acetate [prepared methyl-6H-thieno[2,3- using A from
the methyl 2-(5- b]pyrrol-4-yl)acetic acid
methyl-6H-thieno[2,3-b]pyrrol-4- yl)acetate and the 4-
chlorobenzene-1-sulfonyl chloride] Methyl 2-(5-methyl-6-
2-(5-Methyl-6-(naphthalen- C.1.4 2.19 (b) 386.1 (M + H).sup.+
(phenylsulfonyl)-6H-thieno[2,3- 1-ylsulfonyl)-6H-
b]pyrrol-4-yl)acetate [prepared thieno[2,3-b]pyrrol-4- using A from
the methyl 2-(5- yl)acetic acid methyl-6H-thieno[2,3-b]pyrrol-4-
yl)acetate and the naphthalene-1- sulfonyl chloride] Methyl
2-(5-methyl-6- 2-(5-Methyl-6-(4- C.1.5 2.24 (b) 404.1 (M + H).sup.+
(phenylsulfonyl)-6H-thieno[2,3- (trifluoromethyl)phenylsulfonyl)-
b]pyrrol-4-yl)acetate [prepared 6H-thieno[2,3- using A from the
methyl 2-(5- b]pyrrol-4-yl)acetic acid
methyl-6H-thieno[2,3-b]pyrrol-4- yl)acetate and the 4-
(trifluoromethyl)benzene-1- sulfonyl chloride] Methyl
2-(5-methyl-6- 2-(6-(3,4- C.1.6 2.30 (b) 403.0 (M - H).sup.-
(phenylsulfonyl)-6H-thieno[2,3- Dichlorophenylsulfonyl)-5-
b]pyrrol-4-yl)acetate [prepared methyl-6H-thieno[2,3- using A from
the methyl 2-(5- b]pyrrol-4-yl)acetic acid
methyl-6H-thieno[2,3-b]pyrrol-4- yl)acetate and the 3,4-
dichlorobenzene-1-sulfonyl chloride] Methyl 2-(5-methyl-6-
2-(6-(2,5- C.1.7 2.20 (b) 403.0 (M - H).sup.-
(phenylsulfonyl)-6H-thieno[2,3- Dichlorophenylsulfonyl)-5-
b]pyrrol-4-yl)acetate [prepared methyl-6H-thieno[2,3- using A from
the methyl 2-(5- b]pyrrol-4-yl)acetic acid
methyl-6H-thieno[2,3-b]pyrrol-4- yl)acetate and the 2,5-
dichlorobenzene-1-sulfonyl chloride] Methyl 2-(5-methyl-6-
2-(6-(3,5- C.1.8 2.28 (b) 403.0 (M - H).sup.-
(phenylsulfonyl)-6H-thieno[2,3- Dichlorophenylsulfonyl)-5-
b]pyrrol-4-yl)acetate [prepared methyl-6H-thieno[2,3- using A from
the methyl 2-(5- b]pyrrol-4-yl)acetic acid
methyl-6H-thieno[2,3-b]pyrrol-4- yl)acetate and the 3,5-
dichlorobenzene-1-sulfonyl chloride] Methyl 2-(5-methyl-6-
2-(6-(2,3- C.1.9 2.20 (b) 403.0 (M - H).sup.-
(phenylsulfonyl)-6H-thieno[2,3- Dichlorophenylsulfonyl)-5-
b]pyrrol-4-yl)acetate [prepared methyl-6H-thieno[2,3- using A from
the methyl 2-(5- b]pyrrol-4-yl)acetic acid
methyl-6H-thieno[2,3-b]pyrrol-4- yl)acetate and the 2,3-
dichlorobenzene-1-sulfonyl chloride] Methyl 2-(5-methyl-6- 2-(6-(4-
C.1.10 2.07 (b) 354.1 (M + H).sup.+ (phenylsulfonyl)-6H-thieno[2,3-
Fluorophenylsulfonyl)-5- b]pyrrol-4-yl)acetate [prepared
methyl-6H-thieno[2,3- using A from the methyl 2-(5-
b]pyrrol-4-yl)acetic acid methyl-6H-thieno[2,3-b]pyrrol-4-
yl)acetate and the 4- fluorobenzene-1-sulfonyl chloride] Methyl
2-(5-methyl-6- 2-(5-Methyl-6-(4- C.1.11 2.10 (b) 483.1 (M -
H).sup.- (phenylsulfonyl)-6H-thieno[2,3-
(morpholinosulfonyl)phenylsulfonyl)- b]pyrrol-4-yl)acetate
[prepared 6H-thieno[2,3- using A from the methyl 2-(5-
b]pyrrol-4-yl)acetic acid methyl-6H-thieno[2,3-b]pyrrol-4-
yl)acetate and the 4- (morpholmosulfonyl)benzene-1- sulfonyl
chloride [Matrix]] Methyl 2-(5-methyl-6- 2-(5-Methyl-6-(4- C.1.12
2.10 (b) 467.1 (M - H).sup.- (phenylsulfonyl)-6H-thieno[2,3-
(pyrrolidin-1- b]pyrrol-4-yl)acetate [prepared
ylsulfonyl)phenylsulfonyl)- using A from the methyl 2-(5-
6H-thieno[2,3-b]pyrrol-4- methyl-6H-thieno[2,3-b]pyrrol-4-
yl)acetic acid yl)acetate and the 4-(pyrrolidin-1-
ylsulfonyl)benzene-1-sulfonyl chloride [Matrix]] Methyl
2-(5-methyl-6- 2-(5-Methyl-6-(pyridin-3- C.1.13 1.80 (b) 337.1 (M +
H).sup.+ (phenylsulfonyl)-6H-thieno[2,3- ylsulfonyl)-6H-thieno[2,3-
b]pyrrol-4-yl)acetate [prepared b]pyrrol-4-yl)acetic acid using A
from the methyl 2-(5- methyl-6H-thieno[2,3-b]pyrrol-4- yl)acetate
and the pyridine-3- sulfonyl chloride [Matrix]] Methyl
2-(5-methyl-6- 2-(6-(4- C.1.14 2.00 (b) 359.0 (M - H).sup.-
(phenylsulfonyl)-6H-thieno[2,3- Cyanophenylsulfonyl)-5-
b]pyrrol-4-yl)acetate [prepared methyl-6H-thieno[2,3- using A from
the methyl 2-(5- b]pyrrol-4-yl)acetic acid
methyl-6H-thieno[2,3-b]pyrrol-4- yl)acetate and the 4-
cyanobenzene-1-sulfonyl chloride] Methyl 2-(5-methyl-6-
2-(6-(4-(3,3- C.1.15 1.80 (b) 422.1 (M + H).sup.+
(phenylsulfonyl)-6H-thieno[2,3- Dimethylureido)phenylsulfonyl)-
b]pyrrol-4-yl)acetate [prepared 5-methyl-6H- using A from the
methyl 2-(5- thieno[2,3-b]pyrrol-4-
methyl-6H-thieno[2,3-b]pyrrol-4- yl)acetic acid yl)acetate and the
4-(3,3- dimethylureido)benzene-1- sulfonyl chloride [Oakwood
Products Inc]] Methyl 2-(5-methyl-6- 2-(6-(4- C.1.16 1.90 (b) 393.1
(M + H).sup.+ (phenylsulfonyl)-6H-thieno[2,3-
Acetamidophenylsulfonyl)- b]pyrrol-4-yl)acetate [prepared
5-methyl-6H-thieno[2,3- using A from the methyl 2-(5-
b]pyrrol-4-yl)acetic acid methyl-6H-thieno[2,3-b]pyrrol-4-
yl)acetate and the 4- acetam idobenzene-1-sulfonyl chloride]
TABLE-US-00004 TABLE C.2 Examples of
2-(6-(sulfonyl)-6H-thieno[2,3-b]pyrrol-4-yl)acetic acid prepared
using General Procedure C R.sub.t min Ester Product Example #
(method) m/z ESI Ethyl 2-(6-(4- 2-(6-(4- C.2.1 2.66 (a) 398.2 (M -
H).sup.- (methylsulfonyl)phenylsulfonyl)-
(Methylsulfonyl)phenylsulfonyl)-
6H-thieno[2,3-b]pyrrol-4-yl)acetate 6H- [prepared using A from
ethyl 2-(6H- thieno[2,3-b]pyrrol-4-
thieno[2,3-b]pyrrol-4-yl)acetate and yl)acetic acid
4-(methylsulfonyl)benzene-1- sulfonyl chloride] Ethyl 2-(6-(4-
2-(6-(4- C.2.2 3.12 (a) 354.2 (M - H).sup.-
chlorophenylsulfonyl)-6H- Chlorophenylsulfonyl)-
thieno[2,3-b]pyrrol-4-yl)acetate 6H-thieno[2,3-b]pyrrol- [prepared
using A from ethyl 2-(6H- 4-yl)acetic acid
thieno[2,3-b]pyrrol-4-yl)acetate and 4-chlorobenzene-1-sulfonyl
chloride] Ethyl 2-(6-(2,5- 2-(6-(2,5- C.2.3 3.29 (a) 390.1 (M +
H).sup.+ dichlorophenylsulfonyl)-6H- Dichlorophenylsulfonyl)-
thieno[2,3-b]pyrrol-4-yl)acetate 6H-thieno[2,3- [prepared using A
from ethyl 2-(6H- b]pyrrol-4-yl)acetic
thieno[2,3-b]pyrrol-4-yl)acetate and acid
2,5-dichlorobenzene-1-sulfonyl chloride]
TABLE-US-00005 TABLE C.3 Examples of
2-(3,5-dimethyl-6-(sulfonyl)-6H-thieno[2,3-b]pyrrol-4-yl)acetic
acid acid using General Procedure C R.sub.t min Ester Product
Example # (method) m/z ESI Methyl 2-(6-(3,5- 2-(6-(3,5- C.3.1 2.39
(a) 416.0 (M - H).sup.- dichlorophenylsulfonyl)-3,5-dimethyl-
Dichlorophenylsulfonyl)- 6H-thieno[2,3-b]pyrrol-4-yl)acetate
3,5-dimethyl-6H- [prepared using A from the methyl 2-
thieno[2,3-b]pyrrol-4- (3,5-dimethyl-6H-thieno[2,3-b]pyrrol-
yl)acetic acid 4-yl)acetate and the 3,5- dichlorobenzene-1-sulfonyl
chloride] Methyl 2-(6-(4-fluorophenylsulfonyl)- 2-(6-(4- C.3.2 2.16
(a) 366.0 (M - H).sup.- 3,5-dimethyl-6H-thieno[2,3-b]pyrrol-
Fluorophenylsulfonyl)- 4-yl)acetate [prepared using A from
3,5-dimethyl-6H- the methyl 2-(3,5-dimethyl-6H-
thieno[2,3-b]pyrrol-4- thieno[2,3-b]pyrrol-4-yl)acetate and
yl)acetic acid the 4-fluorobenzene-1-sulfonyl chloride] Methyl
2-(3,5-dimethyl-6-(4- 2-(3,5-Dimethyl-6-(4- C.3.3 1.96 (b) 426.0 (M
- H).sup.- (methylsulfonyl)phenylsulfonyl)-6H-
(methylsulfonyl)phenylsulfonyl)- thieno[2,3-b]pyrrol-4-yl)acetate
6H-thieno[2,3-b]pyrrol-4- [prepared using A from the methyl 2-
yl)acetic acid (3,5-dimethyl-6H-thieno[2,3-b]pyrrol- 4-yl)acetate
and the 4- (methylsulfonyl)benzene-1-sulfonyl chloride] Methyl
2-(3,5-dimethyl-6-(4- 2-(3,5-Dimethyl-6- C.3.4 2.09 (b) 350.1 (M +
H).sup.+ (methylsulfonyl)phenylsulfonyl)-6H- (phenylsulfonyl)-6H-
thieno[2,3-b]pyrrol-4-yl)acetate thieno[2,3-b]pyrrol-4- [prepared
using A from the methyl 2- yl)acetic acid
(3,5-dimethyl-6H-thieno[2,3-b]pyrrol- 4-yl)acetate and the 4-
benzenesulfonyl chloride] Methyl 2-(3,5-dimethyl-6-(4- 2-(6-(4-
C.3.5 2.40 (b) 384.0 (M + H).sup.+
(methylsulfonyl)phenylsulfonyl)-6H- Chlorophenylsulfonyl)-
thieno[2,3-b]pyrrol-4-yl)acetate 3,5-dimethyl-6H- [prepared using A
from the methyl 2- thieno[2,3-b]pyrrol-4-
(3,5-dimethyl-6H-thieno[2,3-b]pyrrol- yl)acetic acid 4-yl)acetate
and the 4-chlorobenzene- 1-sulfonyl chloride] Methyl
2-(3,5-dimethyl-6-(4- 2-(3,5-Dimethyl-6- C.3.6 2.26 (b) 400.1 (M +
H).sup.+ (methylsulfonyl)phenylsulfonyl)-6H- (naphthalen-1-
thieno[2,3-b]pyrrol-4-yl)acetate ylsulfonyl)-6H- [prepared using A
from the methyl 2- thieno[2,3-b]pyrrol-4-
(3,5-dimethyl-6H-thieno[2,3-b]pyrrol- yl)acetic acid 4-yl)acetate
and the naphthalene-1- sulfonyl chloride] Methyl
2-(3,5-dimethyl-6-(4- 2-(3,5-Dimethyl-6-(4- C.3.7 2.28 (b) 418.2 (M
+ H).sup.+ (methylsulfonyl)phenylsulfonyl)-6H-
(trifluoromethyl)phenylsulfonyl)- thieno[2,3-b]pyrrol-4-yl)acetate
6H-thieno[2,3-b]pyrrol-4- [prepared using A from the methyl 2-
yl)acetic acid (3,5-dimethyl-6H-thieno[2,3-b]pyrrol- 4-yl)acetate
and the 4- (trifluoromethyl)benzene-1-sulfonyl chloride]
General Procedure D: Saponification of a
2-(6-benzyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate
[0149] An aqueous solution of a base (such as NaOH, KOH or LiOH,
preferably NaOH) (1-4 mol/L, preferably 1 mol/L) (2-5 equiv,
preferably 2 equiv) is added to a solution of alkyl
2-(6-benzyl-5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate (1 equiv)
in an organic solvent such (MeOH, EtOH, preferably MeOH). The
reaction mixture is stirred at about ambient temperature for about
1-5 h (preferably 3 h). The mixture is diluted with an organic
solvent (such as EtOAc, DCM or Et.sub.2O, preferably DCM) and
washed with water. The aqueous extracts are acidified to pH about
1-3 (preferably pH=3) with a 1N aqueous solution of hydrochloric
acid and extracted with an organic solvent (such as EtOAc, DCM or
Et.sub.2O, preferably DCM). The layers are separated and the
organic solution is dried over a drying agent (such as
Na.sub.2SO.sub.4 or MgSO.sub.4, preferably MgSO.sub.4) filtered and
concentrated under reduced pressure to give the target compound.
Optionally, the product can be purified by trituration with an
organic solvent such as (Et.sub.2O or heptane, preferably
Et.sub.2O).
Illustration of General Procedure D
Example #D.1.1:
5-Methyl-6-(4-(methylsulfonyl)benzyl)-6H-thieno[2,3-b]pyrrol-4-yl)acetic
acid
##STR00024##
[0151] An aqueous solution of NaOH (1 mol/L, 0.620 mL, 0.620 mmol)
was added to a solution of methyl
2-(5-methyl-6-(4-(methylsulfonyl)benzyl)-6H-thieno[2,3-b]pyrrol-4-yl)acet-
ate (0.117 g, 0.310 mmol) in MeOH (3 mL). The reaction mixture was
stirred at ambient temperature for 2 h. The mixture was diluted
with DCM and washed with water. The aqueous extracts were acidified
to about pH 3 with a 1N aqueous solution of hydrochloric acid and
extracted with DCM. The layers were separated and the organic
solution was dried over MgSO.sub.4, filtered, and concentrated
under reduced pressure to give the title compound (0.047 g, 41.7%):
LC/MS (Table 1, Method a) R.sub.t=2.79 min; MS m/z 381
(M+NH.sub.4).sup.+; .sup.1H NMR (CDCl.sub.3) .delta. 7.88 (d, 2H,
J=8.4 Hz), 7.25 (d, 2H, J=8.4 Hz), 6.99 (d, 1H, J=5.2 Hz), 6.78 (d,
1H, J=5.2 Hz), 5.21 (s, 2H), 3.66 (s, 2H), 3.03 (s, 3H), 2.26 (s,
3H).
TABLE-US-00006 TABLE D.1 Examples of
2-(6-benzyl-5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)acetic acids
prepared from using General Procedure D R.sub.t min Ester Product
Example # (method) m/z ESI Methyl 2-(6-(4-tert-butylbenzyl)-
2-(6-(4-tert- D.1.2 2.55 (b) 342.2 (M + H).sup.+
5-methyl-6H-thieno[2,3-b]pyrrol- Butylbenzyl)-5-methyl-
4-yl)acetate [prepared using B 6H-thieno[2,3-b]pyrrol- from the
methyl 2-(5-methyl-6H- 4-yl)acetic acid
thieno[2,3-b]pyrrol-4-yl)acetate and the 1-(bromomethyl)-4-tert-
butylbenzene] Methyl 2-(6-(4-methoxybenzyl)- 2-(6-(4- D.1.3 2.00
(b) 316.1 (M + H).sup.+ 5-methyl-6H-thieno[2,3-b]pyrrol-
Methoxybenzyl)-5- 4-yl)acetate [prepared using B
methyl-6H-thieno[2,3- from the methyl 2-(5-methyl-6H-
b]pyrrol-4-yl)acetic thieno[2,3-b]pyrrol-4-yl)acetate acid and the
1-(chloromethyl)-4- methoxybenzene] Methyl 2-(6-(4-(1H-pyrazol-1-
2-(6-(4-(1H-Pyrazol-1- D.1.4 2.00 (b) 352.1 (M + H).sup.+
yl)benzyl)-5-methyl-6H- yl)benzyl)-5-methyl-
thieno[2,3-b]pyrrol-4-yl)acetate 6H-thieno[2,3-b]pyrrol- [prepared
using B from the methyl 4-yl)acetic acid 2-(5-methyl-6H-thieno[2,3-
b]pyrrol-4-yl)acetate and the 1-(4- (bromomethyl)phenyl)-1H-
pyrazole [Maybridge]] Methyl 2-(6-(2-chloro-4- 2-(6-(2-Chloro-4-
D.1.5 2.55 (b) 398.0 (M + H).sup.+ (methylsulfonyl)benzyl)-5-
(methylsulfonyl)benzyl)- methyl-6H-thieno[2,3-b]pyrrol-4-
5-methyl-6H- yl)acetate [prepared using B from
thieno[2,3-b]pyrrol-4- the methyl 2-(5-methyl-6H- yl)acetic acid
thieno[2,3-b]pyrrol-4-yl)acetate and the 1-(bromomethyl)-2-
chloro-4-(methylsulfonyl)benzene [Oakwood Products Inc]] Methyl
2-(6-(4-(N,N- 2-(6-(4-(N,N- D.1.6 2.46 (b) 393.1 (M + H).sup.+
dimethylsulfamoyl)benzyl)-5- Dimethylsulfamoyl)benzyl)-
methyl-6H-thieno[2,3-b]pyrrol-4- 5-methyl-6H- yl)acetate [prepared
using B from thieno[2,3-b]pyrrol-4- the methyl 2-(5-methyl-6H-
yl)acetic acid thieno[2,3-b]pyrrol-4-yl)acetate and the
4-(bromomethyl)-N,N- dimethylbenzenesulfonamide [AmberMolTech LLC]]
Methyl 2-(6-(4-(N-cyclohexyl-N- 2-(6-(4-(N-Cyclohexyl- D.1.5 2.95
(b) 461.2 (M + H).sup.+ methylsulfamoyl)benzyl)-5- N-
methyl-6H-thieno[2,3-b]pyrrol-4- methylsulfamoyl)benzyl)-
yl)acetate [prepared using B from 5-methyl-6H- the methyl
2-(5-methyl-6H- thieno[2,3-b]pyrrol-4-
thieno[2,3-b]pyrrol-4-yl)acetate yl)acetic acid and the
4-(bromomethyl)-N- cyclohexyl-N-methylbenzene- sulfonamide[prepared
using J with the The 4-(bromo- methyl)benzene-1-sulfonyl chloride
and the N- methylcyclohexanamine]] Methyl 2-(5-methyl-6-(4-
2-(5-Methyl-6-(4- D.1.7 2.43 (b) 435.1 (M + H).sup.+
(morpholinosulfonyl)benzyl)-6H- (morpholinosulfonyl)benzyl)-
thieno[2,3-b]pyrrol-4-yl)acetate 6H-thieno[2,3- [prepared using B
from the methyl b]pyrrol-4-yl)acetic 2-(5-methyl-6H-thieno[2,3-
acid b]pyrrol-4-yl)acetate and the 4-(4-
(bromomethyl)phenylsulfonyl)morpholine [prepared using J from the
4-(bromomethyl)benzene-1- sulfonyl chloride and morpholine]] Methyl
2-(5-methyl-6-((5- 2-(5-Methyl-6-((5- D.1.8 2.35 (a) 291.08 (M +
H).sup.+ methylisoxazol-3-yl)methyl)-6H- methylisoxazol-3-
thieno[2,3-b]pyrrol-4-yl)acetate yl)methyl)-6H- [prepared using B
from the methyl thieno[2,3-b]pyrrol-4- 2-(5-methyl-6H-thieno[2,3-
yl)acetic acid b]pyrrol-4-yl)acetate and the 3-
(bromomethyl)-5-methylisoxazole [Ryan Scientific Product List]
TABLE-US-00007 TABLE D.2 Examples of
2-(6-benzyl-2,5-dimethyl-6H-thieno[2,3-b]pyrrol-4-yl)acetic
acidusing General Procedure D R.sub.t min Ester Product Example #
(method) m/z ESI Methyl 2-(2,5-dimethyl-6-(4- 2-(2,5-Dimethyl-6-(4-
D.2.1 2.38 (a) 376 (M - H).sup.- (methylsulfonyl)benzyl)-6H-
(methylsulfonyl)benzyl)- thieno[2,3-b]pyrrol-4-yl)acetate
6H-thieno[2,3- [prepared using A. from the b]pyrrol-4-yl)acetic
methyl 2-(2,5-dimethyl-6H- acid thieno[2,3-b]pyrrol-4-yl)acetate
and the 1-(chloromethyl)-4- (methylsulfonyl)benzene [Oakwood
Products Inc]] Methyl 2-(6-(2-chloro-4- 2-(6-(2-Chloro-4- D.2.2
2.50 (a) 410 (M - H).sup.- (methylsulfonyl)benzyl)-2,5-
(methylsulfonyl)benzyl)- dimethyl-6H-thieno[2,3-b]pyrrol-
2,5-dimethyl-6H- 4-yl)acetate [prepared using A
thieno[2,3-b]pyrrol-4- from the methyl 2-(2,5-dimethyl- yl)acetic
acid 6H-thieno[2,3-b]pyrrol-4- yl)acetate and the 2-chloro-1-
(bromomethyl)-4- (methylsulfonyl)benzene [Oakwood Products
Inc]]
TABLE-US-00008 TABLE D.3 Examples of
2-(6-benzyl-3,5-dimethyl-6H-thieno[2,3-b]pyrrol-4-yl)acetic acid
acid using General Procedure D R.sub.t min Ester Product Example #
(method) m/z ESI Methyl 2-(3,5-dimethyl-6-(4- 2-(3,5-Dimethyl-6-(4-
D.3.1 1.96 (a) 376 (M - H).sup.- (methylsulfonyl)benzyl)-6H-
(methylsulfonyl)benzyl)- thieno[2,3-b]pyrrol-4-yl)acetate
6H-thieno[2,3-b]pyrrol-4- [prepared using A from the yl)acetic acid
methyl 2-(3,5-dimethyl-6H- thieno[2,3-b]pyrrol-4-yl)acetate and the
1-(chloromethyl)-4- (methylsulfonyl)benzene [Oakwood Products
Inc]]
General Procedure E: Saponification of a
thiophene-2-carboxylate
[0152] To a solution of an appropriately substituted
thiophene-2-carboxylate in an organic solvent (such as dioxane or
THF preferably THF) is added an aqueous solution of a base (such as
NaOH, KOH or LiOH, preferably NaOH) (0.9-2.0 equiv, preferably 1.1
equiv). A protic solvent (such as MeOH or EtOH, preferably MeOH) is
added to the reaction mixture until an homogeneous solution is
obtained. After about 2-8 h (preferably 4 h), an acid (such AcOH or
HCl, as preferably HCl) is added until a pH of about 1 is obtained.
The reaction mixture is partially concentrated and the resulting
solid is collected by filtration and dried in vacuo.
Illustration of General Procedure E:
Preparation #E.1: The 3-iodo-4-methylthiophene-2-carboxylic
acid
##STR00025##
[0154] To a solution of methyl
3-iodo-4-methylthiophene-2-carboxylate [Oakwood Product Inc.] (10
g, 35.4 mmol) in THF (200 mL) was added a solution of 2N NaOH
(19.50 mL, 39.0 mmol). MeOH was added to the reaction mixture until
a homogeneous solution was obtained. After about 4 h, concentrated
HCl was added until a pH of about 1 was obtained. The reaction
mixture was partially concentrated under reduced pressure and the
resulting solid was collected by filtration and dried under reduced
pressure to provide the title compound as a brown solid (9.50 g,
100%): LC/MS (Table 1, Method a) R.sub.t=2.55 min; m/z: 267
(M-H).sup.-.
General Procedure F: Formation of a tert-butyl
thiophen-2-ylcarbamate
[0155] To a solution of an appropriately substituted
thiophene-2-carboxylic acid (preferably 1 equiv) in tert-butanol is
added an amine (Et.sub.3N, N,N-diisopropylamine,
N,N-diisopropylethylamine, preferably Et.sub.3N) (1-3 equiv,
preferably 1 equiv) and diphenyl phosphoryl azide (1-3 equiv,
preferably 1 equiv) at about 15-25.degree. C. (preferably at about
20.degree. C.). The reaction mixture is heated to about 25.degree.
C. to 65.degree. C. to reflux (preferably to about 65.degree. C.)
for about 2-16 h (preferably about 8 h). The volatiles are removed
under reduced pressure and the residue optionally purified by
chromatography on silica gel.
Illustration of General Procedure F
Preparation #F.1: The tert-butyl 5-methylthiophen-2-ylcarbamate
##STR00026##
[0157] To a solution of 5-methylthiophene-2-carboxylic acid (5 g,
35.2 mmol) in tert-butanol (99 mL) was added Et.sub.3N (3.91 g,
38.7 mmol) and diphenyl phosphoryl azide (10.65 g, 38.7 mmol). The
reaction mixture was heated to 65.degree. C. for 4 h, then refluxed
for 4 h. The volatiles were removed under reduced pressure and the
residual crude material was purified by flash chromatography on
silica gel (DCM/MeOH: 98/2) to give the title compound (7 g, 75%):
.sup.1HNMR (DMSO) .delta. 10.10 (s, 1H), 6.43 (d, J=2 Hz, 1H), 6.29
(d, J=2 Hz, 1H), 2.30 (s, 3H), 1.42 (s, 9H).
General Procedure G: Bromination of a tert-butyl
thiophen-2-ylcarbamate
[0158] To a solution of a tert-butyl thiophen-2-ylcarbamate
(preferably 1 equiv) in an alcoholic solvent (MeOH, EtOH, i-PrOH,
preferably MeOH) at about -5 to 5.degree. C. (preferably at about
0.degree. C.) is added a solution of bromine (1-2 equiv, preferably
1 equiv) in an alcoholic solvent (MeOH, EtOH, i-PrOH, preferably
MeOH) during about 1-2 h (preferably about 1 h). The reaction is
stirred at about -5 to 5.degree. C. (preferably at about 0.degree.
C.) for about 15 min to 2 h (preferably about 1 h) and at about 10
to 25.degree. C. (preferably about 20.degree. C.) for about 0.5 to
2 h (preferably about 1 h). The reaction is then poured into water
and the solution is neutralized with an aqueous solution of a base
(such as NaOH, KOH, NaHCO.sub.3, Na.sub.2CO.sub.3, preferably
NaOH). MeOH is removed under reduced pressure and the product is
extracted into an organic solvent (DCM, EtOAc, Et.sub.2O,
preferably DCM). The combined organic phases are dried over a
drying agent (such as MgSO.sub.4, NaSO.sub.4, preferably
MgSO.sub.4). The solvent is removed under reduced pressure to give
the title compound that can optionally be purified by
chromatography on silica gel.
Illustration of General Procedure G
Preparation #G.1: The tert-butyl
3-bromo-5-methylthiophen-2-ylcarbamate
##STR00027##
[0160] To a solution of tert-butyl 5-methylthiophen-2-ylcarbamate
(5.1 g, 23.91 mmol) in MeOH (478 mL) at 0.degree. C. was added drop
wise a solution of bromine (1.232 mL, 23.91 mmol) in MeOH (478 mL)
during 1.5 h. The reaction mixture was then stirred at 0.degree. C.
for 0.5 h and at ambient temperature for 45 min. The reaction was
poured into water (400 mL) and the solution was neutralized with 2
M NaOH (aq). MeOH was removed under reduced pressure and the cloudy
aqueous phase was extracted with DCM (3.times.200 mL). The combined
organic phases were dried over MgSO.sub.4. The solvent was removed
under reduced pressure to give (5.3 g, 76%) of the title compound
that was used in the next step without further purification: LC/MS
(Table 1, Method a) R.sub.t=2.48 min; m/z: 292.1 (M-H).sup.-.
General Procedure H: One pot alkylation/cyclization to a tert-butyl
6H-thieno[2,3-b]pyrrole-6-carboxylates
[0161] To a solution of a tert-butyl 3-bromo- or tert-butyl
3-iodo-thiophen-2-ylcarbamate (preferably 1 equiv) in an organic
solvent (such as DMF, DMA or dioxane, preferably DMF) at ambient
temperature is added a carbonate (such as K.sub.2CO.sub.3, or
Na.sub.2CO.sub.3, preferably K.sub.2CO.sub.3) (1-5 equiv,
preferably 4 equiv) and an (E)-4-bromoalkyl-2-enoate (1-2 equiv,
preferably 2 equiv). The reaction mixture is stirred at ambient
temperature for about 12-18 h (preferably 18 h). Palladium (II)
acetate (0.05-0.10 equiv, preferably 0.05 equiv) and PPh.sub.3
(0.05-0.15 equiv, preferably 0.1 equiv) are added and the reaction
mixture is heated to about 75-100.degree. C. (preferably 85.degree.
C.) for about 4-18 h (preferably 16 h). The crude mixture is
diluted with an organic solvent (such as EtOAc, DCM, or Et.sub.2O,
preferably DCM) and washed with water. The layers are separated and
the organic solution is dried over a drying agent (such as
Na.sub.2SO.sub.4 or MgSO.sub.4, preferably MgSO.sub.4), filtered,
and concentrated under reduced pressure to give the target
compound. Optionally, the product can be purified by chromatography
on silica gel.
Illustration of General Procedure H
Preparation #H.1: the tert-Butyl
4-(2-methoxy-2-oxoethyl)-5-methyl-6H-thieno[2,3-b]pyrrole-6-carboxylate
##STR00028##
[0163] To a solution of tert-butyl 3-bromothiophen-2-ylcarbamate (1
g, 3.59 mmol) in DMF (15 mL) was added K.sub.2CO.sub.3 (1.987 g,
14.38 mmol) and (E)-methyl 4-bromopent-2-enoate (prepared according
to C. Girard et al, TL, vol 30, No. 52, pp 7399-7402, 1989) (1.388
g, 7.19 mmol). The reaction mixture was stirred at ambient
temperature for 16 h. Palladium(II) acetate (0.040 g, 0.180 mmol)
and PPh.sub.3 (0.094 g, 0.359 mmol) were added and the reaction
mixture was heated to 85.degree. C. for 18 h. DCM was added and the
resulting solution was washed with water. The layers were separated
and the organic solution was dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. The crude material was
purified by flash chromatography on silica gel (heptane/EtOAc: 95/5
to 55/45) to give the title compound (0.404 g, 36.3%): LC/MS (Table
1, Method d) R.sub.t=2.40 min; MS m/z 310 (M+H).sup.+; .sup.1H NMR
(CDCl.sub.3) .delta. 6.97 (m, 2H), 3.72 (s, 3H), 3.62 (s, 2H), 2.56
(s, 3H), 1.70 (s, 9H).
General Procedure I: Deprotection of a tert-butyl
6H-thieno[2,3-b]pyrrole-6-carboxylate
[0164] To a solution of a tert-butyl
4-(2-alkoxy-2-oxoethyl)-6H-thieno[2,3-b]pyrrole-6-carboxylate
(preferably 1 equiv) in an organic solvent (such as DCM, EtOAc,
Et.sub.2O, preferably DCM) is added silica gel. The volatiles are
evaporated under reduced pressure and the residue is heated to
about 30 to 100.degree. C. (preferably to about 65.degree. C.)
under vacuum for about 8 to 48 h (preferably about 24 h). The
compound is washed off the silica gel by an organic solvent (such
as DCM, EtOAc, Et.sub.2O, preferably DCM). The residue can
optionally be purified by chromatography on silica gel.
Illustration of General Procedure I
Preparation #E.1: The methyl
2-(2,5-dimethyl-6H-thieno[2,3-b]pyrrol-4-yl)acetate
##STR00029##
[0166] To a solution of tert-butyl
4-(2-methoxy-2-oxoethyl)-2,5-dimethyl-6H-thieno[2,3-b]pyrrole-6-carboxyla-
te (0.790 g, 2.443 mmol) in DCM (13.13 mL) was added 13 mL of
silica gel. The mixture was concentrated under reduced pressure and
the residue was heated to 65.degree. C. under vacuum for 24 h. The
reaction mixture was purified by flash chromatography on silica gel
(EtOAc/heptane 15/85), to give the title compound (0.35 g, 64%):
LC/MS (Table 1, Method a) R.sub.t=2.06 min; MS m/z 222.1
(M-H).sup.-.
General Procedure J: Preparation of
4-(halomethyl)benzenesulfonamides
[0167] A 4-(halomethyl)benzene-1-sulfonyl chloride (such as the
4-(bromomethyl)benzene-1-sulfonyl chloride or
4-(chloromethyl)benzene-1-sulfonyl chloride, preferably
4-(bromomethyl)benzene-1-sulfonyl chloride) (preferably 1 equiv) is
reacted with a primary or secondary amine (1-1.5 equiv, preferably
1.5 equiv) in the presence of a base (such as Et.sub.3N, or
N-methyldiisopropylamine, preferably Et.sub.3N) (1-2 equiv,
preferably 1.5 equiv) in an organic solvent (such as THF or DCM,
preferably THF) at about ambient temperature for about 5-24 h
(preferably 24 h). The crude reaction mixture is diluted with DCM
and washed with water. The organics extracts are dried over a
drying agent (such as Na.sub.2SO.sub.4 or MgSO.sub.4, preferably
MgSO.sub.4), filtered, concentrated under reduced pressure and the
resulting crude material optionally purified by chromatography on
silica gel.
Illustration of General Procedure J: The
4-(bromomethyl)-N-cyclohexyl-N-methylbenzenesulfonamide
##STR00030##
[0169] The 4-(bromomethyl)benzene-1-sulfonyl chloride (1 g, 3.71
mmol), Et.sub.3N (0.776 mL, 5.56 mmol) and N-methylcyclohexylamine
(0.42 g, 3.71 mmol) were reacted overnight in THF (6 mL) at ambient
temperature. The mixture was diluted with DCM and washed with
water. The organics were dried over MgSO.sub.4, filtered,
concentrated and purified by chromatography on silica gel using an
heptane/EtOAc gradient (100/0 to 50/50) to give the title compound
(0.317 g, 24.6%): .sup.1H NMR (CDCl.sub.3) .delta. 7.88-7.77 (d,
2H, J=8.4 Hz), 7.52 (d, 2H, J=8.4 Hz), 4.62 (s, 2H), 3.87-3.60 (m,
1H), 2.75 (s, 3H), 1.79-1.69 (m, 2H), 1.66-1.57 (m, 1H), 1.52-1.50
(m, 1H), 1.30 (m, 4H), 1.14-0.84 (m, 2H)
General Procedure K: Coupling of a 4H-thieno[3,2-b]pyrrole with
sulfonylchlorides
[0170] A solution of alkoxide (tBuOK, tBuONa, NaOEt, NaOMe,
preferably tBuOK) (1-1.5 equiv, preferably 1.2 equiv) is added to a
solution of an alkyl 2-(4H-thieno[3,2-b]pyrrol-6-yl)acetate (1.0
equiv.) in an organic solvent (such as THF or dioxane, preferably
THF). The reaction mixture is stirred or shaken at about ambient
temperature for about 10 min-2 h (preferably, 10 min). A sulfonyl
chloride (1-1.5 equiv, preferably 1.2 equiv) in solution in an
organic solvent (such as such as THF or dioxane, preferably THF) is
added and the mixture stirred or shaken at about ambient
temperature for about 2-6 h (preferably 4 h). An aqueous solution
of a base (such as NaOH, KOH or LiOH preferably NaOH) (1-10 equiv,
preferably 9.5 equiv) is added and the mixture reacted at about
ambient temperature for about 12-24 h (preferably 24 h). The crude
mixture is concentrated under vacuum purified by HPLC.
Illustration of General Procedure K
Example
K.1.1:2-(4-(Cyclopropylsulfonyl)-4H-thieno[3,2-b]pyrrol-6-yl)aceti-
c acid
##STR00031##
[0172] A solution of tBuOK (0.1 mL, 1.2 equiv, 1.0 M in THF) was
added to a solution of ethyl 2-(4H-thieno[3,2-b]pyrrol-6-yl)acetate
(0.024 g, 0.11 mmol, 1.0 equiv.) in THF (0.5 mL) in a 20 mL vial.
This vial was capped and shaken at room temperature for 10 min. To
the mixture a solution of cyclopropanesulfonyl chloride (0.7 mL,
1.2 equiv, 0.2 M in THF) was added and the reaction was shaken at
room temperature for 4 h. After which time NaOH (aqueous) (1.0 mL,
1.0 M, 9.5 equiv) was added and the reaction was shaken at room
temperature overnight. The crude reaction mixture was then
concentrated to dryness under reduced pressure and taken up in 1.5
mL 1:1 DMSO/MeOH and purified by reverse phase HPLC (Table 1,
Method h) to give the title compound (0.001 g, 3.11%): LC/MS (Table
1, Method e) R.sub.t=1.29 min; MS m/z 285.9 (M+H).sup.+.
TABLE-US-00009 TABLE K.1 Examples of
2-(4-(sulfonyl)-4H-thieno[3,2-b]pyrrol-6-yl)acetic acids prepared
from the ethyl 2-(4H-thieno[3,2-b]pyrrol-6-yl)acetate using General
Procedure K R.sub.t min Sulfonyl chloride Product Example #
(method) m/z ESI 2,4,6- 2-(4-(Mesitylsulfonyl)-4H- K.1.2 1.69 (e)
364 (M + H).sup.+ Trimethylbenzene-1- thieno[3,2-b]pyrrol-6-
sulfonyl chloride yl)acetic acid 2,2,4,6,7- 2-(4-(2,2,4,6,7- K.1.3
1.84 (e) 434 (M + H).sup.+ Pentamethyl-2,3- Pentamethyl-2,3-
dihydrobenzofuran-5- dihydrobenzofuran-5- sulfonyl chloride
ylsulfonyl)-4H-thieno[3,2- b]pyrrol-6-yl)acetic acid
4-Methoxy-2,3,6- 2-(4-(4-Methoxy-2,3,6- K.1.4 1.72 (e) 394 (M +
H).sup.+ trimethylbenzene-1- trimethylphenylsulfonyl)- sulfonyl
chloride 4H-thieno[3,2-b]pyrrol-6- yl)acetic acid 4- 2-(4-(4- K.1.5
1.87 (a) 398.0 (M - H).sup.- Methylsulfonylbenzenesulfonyl
(Methylsulfonyl)phenylsulfonyl)- chloride 4H-thieno[3,2-
b]pyrrol-6-yl)acetic acid 4- 2-(4-(4- K.1.6 2.42 (a) 354.0 (M -
H).sup.- Chlorobenzenesulfonyl Chlorophenylsulfonyl)-4H- chloride
thieno[3,2-b]pyrrol-6- yl)acetic acid 2,5- 2-(4-(2,5- K.1.7 2.42
(a) 388.0 (M - H).sup.- Dichlorobenzenesulfonyl
Dichlorophenylsulfonyl)- chloride 4H-thieno[3,2-b]pyrrol-6-
yl)acetic acid 2- 2-(4-(Naphthalen-1- K.1.8 2.49 (a) 370.1 (M -
H).sup.- Naphthalenesulfonyl ylsulfonyl)-4H-thieno[3,2- chloride
b]pyrrol-6-yl)acetic acid 5-Bromo-2- 2-(4-(5-Bromo-2- K.1.10 1.63
(e) 429.0 (M - H).sup.- methoxybenzene-1- methoxyphenylsulfonyl)-
sulfonyl chloride 4H-thieno[3,2-b]pyrrol-6- yl)acetic acid
3-Cyano-4- 2-(4-(3-Cyano-4- K.1.11 1.39 (e) 361.0 (M - H).sup.-
fluorobenzene-1- hydroxyphenylsulfonyl)- sulfonyl chloride
4H-thieno[3,2-b]pyrrol-6- yl)acetic acid 2-Bromo-4,6-
2-(4-(2-Bromo-6-fluoro-4- K.1.12 1.49 (e) 433.0 (M - H).sup.-
difluorobenzene-1- hydroxyphenylsulfonyl)- sulfonyl chloride
4H-thieno[3,2-b]pyrrol-6- yl)acetic acid 2-Bromo-4-
2-(4-(2-Bromo-4- K.1.13 1.45 (e) 415.0 (M - H).sup.-
fluorobenzene-1- hydroxyphenylsulfonyl)- sulfonyl chloride
4H-thieno[3,2-b]pyrrol-6- yl)acetic acid 4-Methoxy-2-
2-(4-(4-Methoxy-2- K.1.14 1.56 (e) 364.0 (M - H).sup.-
methylbenzene-1- methylphenylsulfonyl)-4H- sulfonyl chloride
thieno[3,2-b]pyrrol-6- yl)acetic acid
* * * * *